Markov decision process design: A framework for integrating strategic and operational decisions.

We consider the problem of optimally designing a system for repeated use under uncertainty. We develop a modeling framework that integrates the design and operational phases, which are represented by a mixed-integer program and discounted-cost infinite-horizon Markov decision processes, respectively. We seek to simultaneously minimize the design costs and the subsequent expected operational costs. This problem setting arises naturally in several application areas, as we illustrate through examples. We derive a bilevel mixed-integer linear programming formulation for the problem and perform a computational study to demonstrate that realistic instances can be solved numerically.

Cluster-Based Toxicity Estimation of Osteoradionecrosis Via Unsupervised Machine Learning: Moving Beyond Single Dose-Parameter Normal Tissue Complication Probability by Using Whole Dose-Volume Histograms for Cohort Risk Stratification.

PURPOSE: Given the limitations of extant models for normal tissue complication probability estimation for osteoradionecrosis (ORN) of the mandible, the purpose of this study was to enrich statistical inference by exploiting structural properties of data and provide a clinically reliable model for ORN risk evaluation through an unsupervised-learning analysis that incorporates the whole radiation dose distribution on the mandible. METHODS AND MATERIALS: The analysis was conducted on retrospective data of 1259 patients with head and neck cancer treated at The University of Texas MD Anderson Cancer Center between 2005 and 2015. During a minimum 12-month posttherapy follow-up period, 173 patients in this cohort (13.7%) developed ORN (grades I to IV). The (structural) clusters of mandibular dose-volume histograms (DVHs) for these patients were identified using the K-means clustering method. A soft-margin support vector machine was used to determine the cluster borders and partition the dose-volume space. The risk of ORN for each dose-volume region was calculated based on incidence rates and other clinical risk factors. RESULTS: The K-means clustering method identified 6 clusters among the DVHs. Based on the first 5 clusters, the dose-volume space was partitioned by the soft-margin support vector machine into distinct regions with different risk indices. The sixth cluster entirely overlapped with the others; the region of this cluster was determined by its envelopes. For each region, the ORN incidence rate per preradiation dental extraction status (a statistically significant, nondose related risk factor for ORN) was reported as the corresponding risk index. CONCLUSIONS: This study presents an unsupervised-learning analysis of a large-scale data set to evaluate the risk of mandibular ORN among patients with head and neck cancer. The results provide a visual risk-assessment tool for ORN (based on the whole DVH and preradiation dental extraction status) as well as a range of constraints for dose optimization under different risk levels.

The Association Between Oncology Outreach and Timely Treatment for Rural Patients with Breast Cancer: A Claims-Based Approach.

BACKGROUND: Oncology outreach is a common strategy for increasing rural access to cancer care, where traveling oncologists commute across healthcare settings to extend specialized care. Examining the extent to which physician outreach is associated with timely treatment for rural patients is critical for informing outreach strategies. METHODS: We identified a 100% fee-for-service sample of incident breast cancer patients from 2015 to 2020 Medicare claims and apportioned them into surgery and adjuvant therapy cohorts based on treatment history. We defined an outreach visit as the provision of care by a traveling oncologist at a clinic outside of their primary hospital service area. We used hierarchical logistic regression to examine the associations between patient receipt of preoperative care at an outreach visit (preoperative outreach) and > 60-day surgical delay, and patient receipt of postoperative care at an outreach visit (postoperative outreach) and > 60-day adjuvant delay. RESULTS: We identified 30,337 rural-residing patients who received breast cancer surgery, of whom 4071 (13.4%) experienced surgical delay. Among surgical patients, 14,501 received adjuvant therapy, of whom 2943 (20.3%) experienced adjuvant delay. In adjusted analysis, we found that patient receipt of preoperative outreach was associated with reduced odds of surgical delay (odds ratio [OR] 0.75, 95% confidence interval [CI] 0.61-0.91); however, we found no association between patient receipt of postoperative outreach and adjuvant delay (OR 1.04, 95% CI 0.85-1.25). CONCLUSIONS: Our findings indicate that preoperative outreach is protective against surgical delay. The traveling oncologists who enable such outreach may play an integral role in catalyzing the coordination and timeliness of patient-centered care.

Rural-urban disparities in health care delivery for children with medical complexity and moderating effects of payer, disability, and community poverty.

PURPOSE: Children with medical complexity (CMC) may be at increased risk of rural-urban disparities in health care delivery given their multifaceted health care needs, but these disparities are poorly understood. This study evaluated rural-urban disparities in health care delivery to CMC and determined whether Medicaid coverage, co-occurring disability, and community poverty modified the effects of rurality on care delivery. METHODS: This retrospective cohort study of 2012-2017 all-payer claims data from Colorado, Massachusetts, and New Hampshire included CMC <18 years. Health care delivery measures (ambulatory clinic visits, emergency department visits, acute care hospitalizations, total hospital days, and receipt of post-acute care) were compared for rural- versus urban-residing CMC in multivariable regression models, following established methods to evaluate effect modification. FINDINGS: Of 112,475 CMC, 7307 (6.5%) were rural residing and 105,168 (93.5%) were urban residing. A total of 68.9% had Medicaid coverage, 33.9% had a disability, and 39.7% lived in communities with >20% child poverty. In adjusted analyses, rural-residing CMC received significantly fewer ambulatory visits (risk ratio [RR] = 0.95, 95% confidence interval [CI]: 0.94-0.96), more emergency visits (RR = 1.12, 95% CI: 1.08-1.16), and fewer hospitalization days (RR = 0.90, 95% CI = 0.85-0.96). The estimated modification effects of rural residence by Medicaid coverage, disability, and community poverty were each statistically significant. Differences in the odds of having a hospitalization and receiving post-acute care did not persist after incorporating sociodemographic and clinical characteristics and interaction effects. CONCLUSIONS: Rural- and urban-residing CMC differed in their receipt of health care, and Medicaid coverage, co-occurring disabilities, and community poverty modified several of these effects. These modifying effects should be considered in clinical and policy initiatives to ensure that such initiatives do not widen rural-urban disparities.

Characterizing the Traveling Oncology Workforce and Its Influence on Patient Travel Burden: A Claims-Based Approach.

PURPOSE: Oncology outreach is a common strategy for extending cancer care to rural patients. However, a nationwide characterization of the traveling workforce that enables this outreach is lacking, and the extent to which outreach reduces travel burden for rural patients is unknown. METHODS: This cross-sectional study analyzed a rural (nonurban) subset of a 100% fee-for-service sample of 355,139 Medicare beneficiaries with incident breast, colorectal, and lung cancers. Surgical, medical, and radiation oncologists were linked to patients using Part B claims, and traveling oncologists were identified by observing hospital service area (HSA) transition patterns. We defined oncology outreach as the provision of cancer care by a traveling oncologist outside of their primary HSA. We used hierarchical gamma regression models to examine the separate associations between patient receipt of oncology outreach and one-way patient travel times to chemotherapy, radiotherapy, and surgery. RESULTS: On average, 9,935 of 39,960 oncologists conducted annual outreach, where 57.8% traveled with low frequency (0-1 outreach visits/mo), 21.1% with medium frequency (1-3 outreach visits/mo), and 21.1% with high frequency (>3 outreach visits/mo). Oncologists provided surgery, radiotherapy, and chemotherapy to 51,715, 27,120, and 5,874 rural beneficiaries, respectively, of whom 2.5%, 6.9%, and 3.6% received oncology outreach. Rural patients who received oncology outreach traveled 16% (95% CI, 11 to 21) and 11% (95% CI, 9 to 13) less minutes to chemotherapy and radiotherapy than those who did not receive oncology outreach, corresponding to expected one-way savings of 15.9 (95% CI, 15.5 to 16.4) and 11.9 (95% CI, 11.7 to 12.2) minutes, respectively. CONCLUSION: Our study introduces a novel claims-based approach for tracking the nationwide traveling oncology workforce and supports oncology outreach as an effective means for improving rural access to cancer care.

Leigh syndrome: an adult presentation of a paediatric disease.

A previously healthy 27-year-old man was admitted to the acute neurology ward with events involving his face, throat and upper limb, which video telemetry later confirmed were refractory focal seizures. He also had progressive pyramidal features, dysarthria and ataxia. MR scans of the brain identified progressive bilateral basal ganglia abnormalities, consistent with Leigh syndrome. However, extensive laboratory and genetic panels did not give a unifying diagnosis. A skeletal muscle biopsy showed no histopathological abnormalities on routine stains. Sequencing of the entire mitochondrial genome in skeletal muscle identified a well-characterised pathogenic variant (m.10191T>C in MT-ND3; NC_012920.1) at 85% heteroplasmy in skeletal muscle. We discuss the clinical and molecular diagnosis of an adult presenting with Leigh syndrome, which is more commonly a paediatric presentation of mitochondrial disease, and how early recognition of a mitochondrial cause is important to support patient care.

Specialties Providing Ambulatory Care and Associated Health Care Utilization and Quality for Children With Medical Complexity.

OBJECTIVE: Although children with medical complexity (CMC) have substantial health care needs, the extent to which they receive ambulatory care from primary care versus specialist clinicians is unknown. We aimed to determine the predominant specialty providing ambulatory care to CMC (primary care or specialty discipline), the extent to which specialists deliver well-child care, and associations between having a specialty predominant provider and health care utilization and quality. METHODS: In a retrospective cohort analysis of 2012-17 all-payer claims data from Colorado, New Hampshire, and Massachusetts, we identified the predominant specialty providing ambulatory care for CMC <18 years. Propensity score weighting was used to create a balanced sample of CMC and assess differences in outcomes, including adequate well-child care, continuity of care, emergency visits, and hospitalizations, between CMC with a primary care versus specialty predominant provider. RESULTS: Among 67,218 CMC, 75.3% (n = 50,584) received the plurality of care from a primary care discipline. Body system involvement, age > 2 years, urban residence, and cooccurring disabilities were associated with predominantly receiving care from specialists. After propensity score weighting, there were no significant differences between CMC with a primary care or specialist "predominant specialty seen" (PSS) in ambulatory visit counts, adequate well-child care, hospitalizations, or overall continuity of care. Specialists were the sole providers of well-child care and vaccines for 49.9% and 53.1% of CMC with a specialist PSS. CONCLUSIONS: Most CMC received the plurality of care from primary care disciplines, and there were no substantial differences in overall utilization or quality based on the PSS.

Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.

Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.

Cluster-Based Toxicity Estimation of Osteoradionecrosis via Unsupervised Machine Learning: Moving Beyond Single Dose-Parameter Normal Tissue Complication Probability by Using Whole Dose-Volume Histograms for Cohort Risk Stratification.

Purpose: Given the limitations of extant models for normal tissue complication probability estimation for osteoradionecrosis (ORN) of the mandible, the purpose of this study was to enrich statistical inference by exploiting structural properties of data and provide a clinically reliable model for ORN risk evaluation through an unsupervised-learning analysis. Materials and Methods: The analysis was conducted on retrospective data of 1,259 head and neck cancer (HNC) patients treated at the University of Texas MD Anderson Cancer Center between 2005 and 2015. The (structural) clusters of mandibular dose-volume histograms (DVHs) were identified through the K-means clustering method. A soft-margin support vector machine (SVM) was used to determine the cluster borders and partition the dose-volume space. The risk of ORN for each dose-volume region was calculated based on the clinical risk factors and incidence rates. Results: The K-means clustering method identified six clusters among the DVHs. Based on the first five clusters, the dose-volume space was partitioned almost perfectly by the soft-margin SVM into distinct regions with different risk indices. The sixth cluster overlapped the others entirely; the region of this cluster was determined by its envelops. These regions and the associated risk indices provide a range of constraints for dose optimization under different risk levels. Conclusion: This study presents an unsupervised-learning analysis of a large-scale data set to evaluate the risk of mandibular ORN among HNC patients. The results provide a visual risk-assessment tool (based on the whole DVH) and a spectrum of dose constraints for radiation planning.

Texas Hospitals' Perspectives About NICU Performance Measures: A Mixed-Methods Study.

BACKGROUND AND OBJECTIVES: This study was conducted to assess Texas hospital leaders' perspectives about neonatal intensive care (NICU) performance measures. METHODS: We conducted an explanatory mixed-methods study. First, we sent a survey and a copy of the Dartmouth Atlas of Neonatal Intensive Care to clinical and administrative leaders of 150 NICUs in Texas. We asked respondents to review the chapter that reported Texas-specific results and respond to a variety of open and closed-ended questions about the overall usefulness of the report. Second, we conducted semistructured qualitative interviews with a subset of survey respondents to better understand their perspectives. RESULTS: The survey had a 50% hospital response rate. Respondents generally found the report to be interesting and useful, and 87.7% of all respondents reported being in favor of receiving future reports with their own hospital's data benchmarked against anonymous peers. All of the specific measures in the Atlas were found to be of interest and valuable, with NICU admissions and special care days rating among the most interesting and useful. In the semistructured interviews, respondents expressed that a report with performance data would serve as a mechanism to drive change by identifying opportunities for improvement. CONCLUSION: Texas hospital NICU leaders are interested in routinely receiving more information about their own NICU's performance anonymously benchmarked against their peers. This would facilitate a greater understanding of a unit's functionality, as well as accelerate clinically appropriate quality improvement initiatives, which together have the potential to deliver better newborn care at lower costs for all Texans.

Optimized decision support for selection of transoral robotic surgery or (chemo)radiation therapy based on posttreatment swallowing toxicity.

BACKGROUND: A primary goal in transoral robotic surgery (TORS) for oropharyngeal squamous cell cancer (OPSCC) survivors is to optimize swallowing function. However, the uncertainty in the outcomes of TORS including postoperative residual positive margin (PM) and extranodal extension (ENE), may necessitate adjuvant therapy, which may cause significant swallowing toxicity to survivors. METHODS: A secondary analysis was performed on a prospective registry data with low- to intermediate-risk human papillomavirus-related OPSCC possibly resectable by TORS. Decision trees were developed to model the uncertainties in TORS compared with definitive radiation therapy (RT) and chemoradiation therapy (CRT). Swallowing toxicities were measured by Dynamic Imaging Grade of Swallowing Toxicity (DIGEST), MD Anderson Dysphagia Inventory (MDADI), and the MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) instruments. The likelihoods of PM/ENE were varied to determine the thresholds within which each therapy remains optimal. RESULTS: Compared with RT, TORS resulted in inferior swallowing function for moderate likelihoods of PM/ENE (>60% in short term for all instruments, >75% in long term for DIGEST and MDASI) leaving RT as the optimal treatment. Compared with CRT, TORS remained the optimal therapy based on MDADI and MDASI but showed inferior swallowing outcomes based on DIGEST for moderate-to-high likelihoods of PM/ENE (>75% for short-term and >40% for long-term outcomes). CONCLUSION: In the absence of reliable estimation of postoperative PM/ENE concurrent with significant postoperative PM, the overall toxicity level in OPSCC patients undergoing TORS with adjuvant therapy may become more severe compared with patients receiving nonsurgical treatments thus advocating definitive (C)RT protocols.

Changing faces of mitochondrial disease: autosomal recessive POLG disease mimicking myasthenia gravis and progressive supranuclear palsy.

Background: Mitochondrial disorders are known to cause diverse neurological phenotypes which cause a diagnostic challenge to most neurologists. Pathogenic polymerase gamma (POLG) variants have been described as a cause of chronic progressive external ophthalmoplegia, which manifests with ptosis, horizontal and vertical eye movement restriction and myopathy. Autosomal dominant progressive external ophthalmoplegia is rarely associated with Parkinsonism responsive to levodopa. Methods: We report a case of a 58-year-old man who presented with an eye movement disorder then Parkinsonism who made his way through the myasthenia then the movement disorder clinic. Results: A diagnostic right tibialis anterior biopsy revealed classical hallmarks of mitochondrial disease, and genetic testing identified compound heterozygous pathogenic gene variants in the POLG gene. The patient was diagnosed with autosomal recessive POLG disease. Conclusions: It is important to maintain a high index of suspicion of pathogenic POLG variants in patients presenting with atypical Parkinsonism and ophthalmoplegia. Patients with POLG-related disease will usually have ptosis, and downgaze is typically preserved until late in the disease. Accurate diagnosis is essential for appropriate prognosis and genetic counselling.

Use of a Novel Network-Based Linchpin Score to Characterize Accessibility to the Oncology Physician Workforce in the United States.

Importance: Physician headcounts provide useful information about the cancer care delivery workforce; however, efforts to track the oncology workforce would benefit from new measures that capture how essential a physician is for meeting the multidisciplinary cancer care needs of the region. Physicians are considered linchpins when fewer of their peers are connected to other physicians of the same specialty as the focal physician. Because they are locally unique for their specialty, these physicians' networks may be particularly vulnerable to their removal from the network (eg, through relocation or retirement). Objective: To examine a novel network-based physician linchpin score within nationwide cancer patient-sharing networks and explore variation in network vulnerability across hospital referral regions (HRRs). Design, Setting, and Participants: This cross-sectional study analyzed fee-for-service Medicare claims and included Medicare beneficiaries with an incident diagnosis of breast, colorectal, or lung cancer from 2016 to 2018 and their treating physicians. Data were analyzed from March 2022 to October 2022. Exposures: Physician characteristics assessed were specialty, rurality, and Census region. HRR variables assessed include sociodemographic and socioeconomic characteristics and use of cancer services. Main Outcomes and Measures: Oncologist linchpin score, which examined the extent to which a physician's peers were connected to other physicians of the same specialty as the focal physician. Network vulnerability, which distinguished HRRs with more linchpin oncologists than expected based on oncologist density. χ2 and Fisher exact tests were used to examine relationships between oncologist characteristics and linchpin score. Spearman rank correlation coefficient (ρ) was used to measure the strength and direction of relationships between HRR network vulnerability, oncologist density, population sociodemographic and socioeconomic characteristics, and cancer service use. Results: The study cohort comprised 308 714 patients with breast, colorectal, or lung cancer. The study cohort of 308 714 patients included 161 206 (52.2%) patients with breast cancer, 76 604 (24.8%) patients with colorectal cancer, and 70 904 (23.0%) patients with lung cancer. In our sample, 272 425 patients (88%) were White, and 238 603 patients (77%) lived in metropolitan areas. The cancer patient-sharing network included 7221 medical oncologists and 3573 radiation oncologists. HRRs with more vulnerable networks for medical oncology had a higher percentage of beneficiaries eligible for Medicaid (ρ, 0.19; 95% CI, 0.08 to 0.29). HRRs with more vulnerable networks for radiation oncology had a higher percentage of beneficiaries living in poverty (ρ, 0.17; 95% CI, 0.06 to 0.27), and a higher percentage of beneficiaries eligible for Medicaid (ρ, 0.21; 95% CI, 0.09 to 0.31), and lower rates of cohort patients receiving radiation therapy (ρ, -0.18; 95% CI, -0.28 to -0.06; P = .003). The was no association between network vulnerability for medical oncology and percent of cohort patients receiving chemotherapy (ρ, -0.03; 95% CI, -0.15 to 0.08). Conclusions and Relevance: This study found that patient-sharing network vulnerability was associated with poverty and lower rates of radiation therapy. Health policy strategies for addressing network vulnerability may improve access to interdisciplinary care and reduce treatment disparities.

Identification of a novel heterozygous DYSF variant in a large family with a dominantly-inherited dysferlinopathy.

AIMS: Dysferlinopathy is an autosomal recessive muscular dystrophy, caused by bi-allelic variants in the gene encoding dysferlin (DYSF). Onset typically occurs in the second to third decade and is characterised by slowly progressive skeletal muscle weakness and atrophy of the proximal and/or distal muscles of the four limbs. There are rare cases of symptomatic DYSF variant carriers. Here, we report a large family with a dominantly inherited hyperCKaemia and late-onset muscular dystrophy. METHODS AND RESULTS: Genetic analysis identified a co-segregating novel DYSF variant [NM_003494.4:c.6207del p.(Tyr2070Metfs*4)]. No secondary variants in DYSF or other dystrophy-related genes were identified on whole genome sequencing and analysis of the proband's DNA. Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. All individuals heterozygous for the c.6207del variant had hyperCKaemia. Histological analysis of skeletal muscle biopsies across three generations showed clear dystrophic signs, including inflammatory infiltrates, regenerating myofibres, increased variability in myofibre size and internal nuclei. Muscle magnetic resonance imaging revealed fatty replacement of muscle in two individuals. Western blot and immunohistochemical analysis of muscle biopsy demonstrated consistent reduction of dysferlin staining. Allele-specific quantitative PCR analysis of DYSF mRNA from patient muscle found that the variant, localised to the extreme C-terminus of dysferlin, does not activate post-transcriptional mRNA decay. CONCLUSIONS: We propose that this inheritance pattern may be underappreciated and that other late-onset muscular dystrophy cases with mono-allelic DYSF variants, particularly C-terminal premature truncation variants, may represent dominant forms of disease.

Rural-Urban Differences in Breast Cancer Surgical Delays in Medicare Beneficiaries.

BACKGROUND: Delays between breast cancer diagnosis and surgery are associated with worsened survival. Delays are more common in urban-residing patients, although factors specific to surgical delays among rural and urban patients are not well understood. METHODS: We used a 100% sample of fee-for-service Medicare claims during 2007-2014 to identify 238,491 women diagnosed with early-stage breast cancer undergoing initial surgery and assessed whether they experienced biopsy-to-surgery intervals > 90 days. We employed multilevel regression to identify associations between delays and patient, regional, and surgeon characteristics, both in combined analyses and stratified by rurality of patient residence. RESULTS: Delays were more prevalent among urban patients (2.5%) than rural patients (1.9%). Rural patients with medium- or high-volume surgeons had lower odds of delay than patients with low-volume surgeons (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.58-0.88; OR = 0.74, 95% CI = 0.61-0.90). Rural patients whose surgeon operated at ≥ 3 hospitals were more likely to experience delays (OR = 1.29, 95% CI = 1.01-1.64, Ref: 1 hospital). Patient driving times ≥ 1 h were associated with delays among urban patients only. Age, black race, Hispanic ethnicity, multimorbidity, and academic/specialty hospital status were associated with delays. CONCLUSIONS: Sociodemographic, geographic, surgeon, and facility factors have distinct associations with > 90-day delays to initial breast cancer surgery. Interventions to improve timeliness of breast cancer surgery may have disparate impacts on vulnerable populations by rural-urban status.

Prevalence of Children With Medical Complexity and Associations With Health Care Utilization and In-Hospital Mortality.

Importance: Children with medical complexity (CMC) have substantial health care needs and frequently experience poor health care quality. Understanding the population prevalence and associated health care needs can inform clinical and public health initiatives. Objective: To estimate the prevalence of CMC using open-source pediatric algorithms, evaluate performance of these algorithms in predicting health care utilization and in-hospital mortality, and identify associations between medical complexity as defined by these algorithms and clinical outcomes. Design, Setting, and Participants: This retrospective cohort study used all-payer claims data from Colorado, Massachusetts, and New Hampshire from 2012 through 2017. Children and adolescents younger than 18 years residing in these states were included if they had 12 months or longer of enrollment in a participating health care plan. Analyses were conducted from March 12, 2021, to January 7, 2022. Exposures: The pediatric Complex Chronic Condition Classification System, Pediatric Medical Complexity Algorithm, and Children With Disabilities Algorithm were applied to 3 years of data to identify children with complex and disabling conditions, first in their original form and then using more conservative criteria that required multiple health care claims or involvement of 3 or more body systems. Main Outcomes and Measures: Primary outcomes, examined over 2 years, included in-hospital mortality and a composite measure of health care services, including specialized therapies, specialized medical equipment, and inpatient care. Outcomes were modeled using logistic regression. Model performance was evaluated using C statistics, sensitivity, and specificity. Results: Of 1 936 957 children, 48.4% were female, 87.8% resided in urban core areas, and 45.1% had government-sponsored insurance as their only primary payer. Depending on the algorithm and coding criteria applied, 0.67% to 11.44% were identified as CMC. All 3 algorithms had adequate discriminative ability, sensitivity, and specificity to predict in-hospital mortality and composite health care services (C statistic = 0.76 [95% CI, 0.73-0.80] to 0.81 [95% CI, 0.78-0.84] for mortality and 0.77 [95% CI, 0.76-0.77] to 0.80 [95% CI, 0.79-0.80] for composite health care services). Across algorithms, CMC had significantly greater odds of mortality (adjusted odds ratio [aOR], 9.97; 95% CI, 7.70-12.89; to aOR, 69.35; 95% CI, 52.52-91.57) and composite health care services (aOR, 4.59; 95% CI, 4.44-4.73; to aOR, 18.87; 95% CI, 17.87-19.93) than children not identified as CMC. Conclusions and Relevance: In this study, open-source algorithms identified different cohorts of CMC in terms of prevalence and magnitude of risk, but all predicted increased health care utilization and in-hospital mortality. These results can inform research, programs, and policies for CMC.

MR-Guided Adaptive Radiotherapy for OAR Sparing in Head and Neck Cancers.

MR-linac devices offer the potential for advancements in radiotherapy (RT) treatment of head and neck cancer (HNC) by using daily MR imaging performed at the time and setup of treatment delivery. This article aims to present a review of current adaptive RT (ART) methods on MR-Linac devices directed towards the sparing of organs at risk (OAR) and a view of future adaptive techniques seeking to improve the therapeutic ratio. This ratio expresses the relationship between the probability of tumor control and the probability of normal tissue damage and is thus an important conceptual metric of success in the sparing of OARs. Increasing spatial conformity of dose distributions to target volume and OARs is an initial step in achieving therapeutic improvements, followed by the use of imaging and clinical biomarkers to inform the clinical decision-making process in an ART paradigm. Pre-clinical and clinical findings support the incorporation of biomarkers into ART protocols and investment into further research to explore imaging biomarkers by taking advantage of the daily MR imaging workflow. A coherent understanding of this road map for RT in HNC is critical for directing future research efforts related to sparing OARs using image-guided radiotherapy (IGRT).

Forecasting stroke-like episodes and outcomes in mitochondrial disease.

In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource. The primary outcome was to interrogate the clinico-radiopathological correlates and prognostic indicators of stroke-like episode in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). The secondary objective was to develop a multivariable prediction model to forecast stroke-like episode risk. The most common genetic cause of stroke-like episodes was the m.3243A>G variant in MT-TL1 (n = 66), followed by recessive pathogenic POLG variants (n = 22), and 11 other rarer pathogenic mitochondrial DNA variants (n = 23). The age of first stroke-like episode was available for 105 patients [mean (SD) age: 31.8 (16.1)]; a total of 35 patients (32%) presented with their first stroke-like episode ≥40 years of age. The median interval (interquartile range) between first and second stroke-like episodes was 1.33 (2.86) years; 43% of patients developed recurrent stroke-like episodes within 12 months. Clinico-radiological, electrophysiological and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy. Patients with POLG-related stroke-like episodes demonstrated more fulminant disease trajectories than cases of m.3243A>G and other mitochondrial DNA pathogenic variants, in terms of the frequency of refractory status epilepticus, rapidity of progression and overall mortality. In multivariate analysis, baseline factors of body mass index, age-adjusted blood m.3243A>G heteroplasmy, sensorineural hearing loss and serum lactate were significantly associated with risk of stroke-like episodes in patients with the m.3243A>G variant. These factors informed the development of a prediction model to assess the risk of developing stroke-like episodes that demonstrated good overall discrimination (area under the curve = 0.87, 95% CI 0.82-0.93; c-statistic = 0.89). Significant radiological and pathological features of neurodegeneration were more evident in patients harbouring pathogenic mtDNA variants compared with POLG: brain atrophy on cranial MRI (90% versus 44%, P < 0.001) and reduced mean brain weight (SD) [1044 g (148) versus 1304 g (142), P = 0.005]. Our findings highlight the often idiosyncratic clinical, radiological and EEG characteristics of mitochondrial stroke-like episodes. Early recognition of seizures and aggressive instigation of treatment may help circumvent or slow neuronal loss and abate increasing disease burden. The risk-prediction model for the m.3243A>G variant can help inform more tailored genetic counselling and prognostication in routine clinical practice.

Cytopenias After CD19 Chimeric Antigen Receptor T-Cells (CAR-T) Therapy for Diffuse Large B-Cell Lymphomas or Transformed Follicular Lymphoma: A Single Institution Experience.

INTRODUCTION: Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have poor outcomes. Treatment with CD19 chimeric antigen receptor (CAR-T) cells, tisagenlecleucel and axicabtagene ciloleucel, has been associated with improved outcomes. Cytopenias were observed in clinical trials with both products; however, little is known regarding the patterns and outcomes of these cytopenias. SUBJECTS AND METHODS: We reviewed DLBCL patients (n=32) receiving either product between January and September 2018 at our institution. RESULTS: Median duration of leukopenia, neutropenia, lymphopenia, anemia, and thrombocytopenia was 49, 9, 117.5, 125, and 95.5 days after CAR-T infusion, respectively. Filgrastim was used in 63% of patients, and 50% of patients received red cell or platelet transfusions. With the exception of neutropenia, increase in the duration of cytopenia of any lineage was associated with improvement in progression-free survival, and in overall survival in case of anemia. There was no association between the duration of cytopenias with either cytokine release syndrome or neurotoxicity. DISCUSSION: Our data suggest a correlation between cytopenias and survival outcomes after CD19 CAR-T therapy. If validated, cytopenia may be proven useful as a biomarker of response and survival after CAR-T therapy.

The three-spin intermediate at the O-O cleavage and proton-pumping junction in heme-Cu oxidases.

Understanding the mechanistic coupling of molecular oxygen reduction and proton pumping for adenosine triphosphate synthesis during cellular respiration is the primary goal of research on heme-copper oxidases­the terminal complex in the membrane-bound electron transport chain. Cleavage of the oxygen-oxygen bond by the heme-copper oxidases forms the key intermediate PM, which initiates proton pumping. This intermediate is now experimentally defined by variable-temperature, variable-field magnetic circular dichroism spectroscopy on a previously unobserved excited state feature associated with its heme iron(IV)-oxo center. These data provide evidence that the iron(IV)-oxo in PM is magnetically coupled to both a copper(II) and a cross-linked tyrosyl radical in the active site. These results provide new insight into the oxygen-oxygen bond cleavage and proton-pumping mechanisms of heme-copper oxidases.