Recurrent diffuse alveolar hemorrhage and extracorporeal membrane oxygenation utilization in a hematopoietic stem cell transplant patient with Hunter's syndrome.

We describe the natural history of a three-month-old patient with Hunter Syndrome with hematopoietic stem cell transplant (HSCT) who developed recurrent diffuse alveolar hemorrhage (DAH) requiring extracorporeal membrane oxygenation (ECMO). The patient underwent HSCT with several complications, including veno-occlusive disease and DAH. He was managed with ECMO. Unfortunately, despite initial success he developed recurrent DAH and ultimately died. This is a novel report of this severe adverse event requiring ECMO following the use of HSCT in this rare patient population. We share the clinical strategies employed to address the complications associated with HSCT and the progression of his disease over his hospitalization.

Additive Manufacturing: A Comprehensive Review.

Additive manufacturing has revolutionized manufacturing across a spectrum of industries by enabling the production of complex geometries with unparalleled customization and reduced waste. Beginning as a rapid prototyping tool, additive manufacturing has matured into a comprehensive manufacturing solution, embracing a wide range of materials, such as polymers, metals, ceramics, and composites. This paper delves into the workflow of additive manufacturing, encompassing design, modeling, slicing, printing, and post-processing. Various additive manufacturing technologies are explored, including material extrusion, VAT polymerization, material jetting, binder jetting, selective laser sintering, selective laser melting, direct metal laser sintering, electron beam melting, multi-jet fusion, direct energy deposition, carbon fiber reinforced, laminated object manufacturing, and more, discussing their principles, advantages, disadvantages, material compatibilities, applications, and developing trends. Additionally, the future of additive manufacturing is projected, highlighting potential advancements in 3D bioprinting, 3D food printing, large-scale 3D printing, 4D printing, and AI-based additive manufacturing. This comprehensive survey aims to underscore the transformative impact of additive manufacturing on global manufacturing, emphasizing ongoing challenges and the promising horizon of innovations that could further elevate its role in the manufacturing revolution.

An Ergonomics Analysis of Archers through Motion Tracking to Prevent Injuries and Improve Performance.

Archery ranks among the sports with a high incidence of upper extremity injuries, particularly affecting the drawing shoulder and elbow, as well as inducing stress on the lower back. This study seeks to bridge the gap by integrating real-time human motion with biomechanical software to enhance the ergonomics of archers. Thirteen participants were involved in four tasks, using different bows with varied draw weights and shooting distances. Through the application of advanced integrative technology, this study highlights the distinct postures adopted by both males and females, which indicate the biomechanical differences between genders. Additionally, an analysis of the correlation between exposed spinal forces and these adopted postures provides insights into injury risk assessment during the key archery movements. The findings of this study have the potential to significantly enhance the application of training methodologies and the design of assistive devices. These improvements are geared towards mitigating injury risks and enhancing the overall performance of archers.

Nitrogen Heterocycle Synthesis through Hydride Abstraction of Acyclic Carbamates and Related Species: Scope, Mechanism, Stereoselectivity, and Product Conformation Studies.

Acyliminium ions and related species are potent electrophiles that can be quite valuable in the synthesis of nitrogen-containing molecules. This manuscript describes a protocol to form these intermediates through hydride abstractions of easily accessible allylic carbamates, amides, and sulfonamides that avoids the reversibility that is possible in classical condensation-based routes. These intermediates are used in the preparation of a range of nitrogen-containing heterocycles, and in many cases high levels of stereocontrol are observed. Specifically areas of investigation include the impact of chemical structure on oxidation efficiency, the geometry of the intermediate iminium ions, the impact of a substrate stereocenter on stereocontrol, and an examination of transition state geometry.

The nature of embryonic mosaicism across female age spectrum: an analysis of 21,345 preimplantation genetic testing for aneuploidy cycles.

Objective: To understand how mosaicism varies across patient-specific variables and clinics. Design: Cross-sectional cohort. Setting: Genetic testing laboratory. Patients: A total of 86,208 embryos from 17,366 patients underwent preimplantation genetic testing for aneuploidy using next-generation sequencing. Interventions: Mosaic embryos were classified as either low-level (20%-40%) or high-level (40%-80%) and by type of mosaic error: single segmental, complex segmental, single chromosome, or complex abnormal mosaic. The rate of mosaicism was stratified by the Society for Assisted Reproductive Technology age categories: <35 years, 35-37 years, 38-40 years, 41-42 years, and >42 years. Main Outcome Measures: Distribution of chromosomal findings and prevalence of mosaicism type by age. Probability of creating mosaic embryos in a subsequent cycle. Results: Among all embryos, 44% were euploid, 40.2% were aneuploid, and 15.8% were mosaic. Both low-level and high-level mosaicism were more prevalent among younger patients. Of all mosaic embryos, the youngest age cohort <35 years had the highest proportions of single and complex segmental mosaicism (37.9% and 6.8%, respectively), whereas those aged >42 years had the highest single whole chromosome and complex abnormal mosaicism (37.1% and 34.0%, respectively). Although there was variability in mosaic rates across clinics, the median mosaic rate over 3 years ranged from 14.48% to 17.72%. A diagnosis of a mosaic embryo in a previous cycle did not increase a patient's odds for having a mosaic embryo in a subsequent cycle. Conclusions: Mosaicism is overall higher in younger patients, but the complexity of mosaic errors increases with age. A history of mosaicism was not associated with mosaicism in subsequent cycles. Additional research is needed to understand the etiologies of the various subtypes of mosaic embryos and clinical outcomes associated with their transfer.

Definition and Clinical Evaluation for Trimethoprim-Sulfamethoxazole Severe Acute Respiratory Failure.

OBJECTIVES: Trimethoprim-sulfamethoxazole (TMP-SMX)-associated severe acute respiratory distress syndrome (ARDS) has gone underrecognized. We propose the first disease definition and clinical evaluation for a novel adverse drug reaction (ADR) based on a series of recently identified rare cases of life-threatening ADRs. DESIGN: A retrospective study was conducted. All medical records were evaluated. Available pathology samples were sent to Massachusetts General for clinical consultation. Blood samples from surviving patients were obtained and human leukocyte antigen (HLA) analysis was performed by the Children's Mercy Hospital Genomic Center and Vanderbilt University Medical Center. SETTING: U.S. ICUs, 1996-2021. PATIENTS: Nineteen young patients (10-37) were identified. Patients were previously healthy, with no preexisting pulmonary disease, no other cause for respiratory failure, and no chronic history of smoking/vaping. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Through our retrospective analysis, we analyzed clinical characteristics associated with TMP-SMX. Pathology samples were reviewed, and HLA analysis was performed on available samples by the study team or as standard of care at treatment hospitals in some cases. In 19 critically ill patients, we identified a pattern of severe respiratory failure requiring ICU admission, mechanical ventilation, and frequent extracorporeal membrane oxygenation use. We describe the first three-part clinical diagnosis and evaluation strategy: 1) Clinical definition: Unexplained severe respiratory failure in a patient receiving greater than or equal to 6 days of TMP-SMX at treatment dose (not prophylaxis). TMP-SMX ARDS is a diagnosis of exclusion. 2) Genetic association: One hundred percent of currently available TMP-SMX respiratory failure patient genomic data, ( n = 11) have been carriers of both HLA-B*07:02 and HLA-C*07:02 alleles. HLA allele evaluation could be considered in patients with suspected TMP-SMX respiratory failure. 3) Lung pathology: A unique pulmonary pathologic pattern of lung injury termed diffuse alveolar injury with delayed epithelialization has been observed in these cases. In suspected cases, surgical lung biopsy early in the clinical course could be considered. CONCLUSIONS: TMP-SMX is a commonly prescribed antibiotic. However, we find it imperative to share this relatively rare but life-threatening condition with clinicians as the mortality rate approaches 40%.

Computed Tomography Coronary Angiography on a Detector-Based Spectral Computed Tomography Platform: Evaluation of Patients With Coronary Artery Disease Reporting and Data System Score of 3 and Higher.

PURPOSE: Computed tomography (CT) coronary angiography performed on a detector-based spectral scanner helps more closely approximate severity of stenosis with nuclear medicine and cardiac catheterization tests compared with single-energy CT (SECT) in patients with an original CAD-RADS score of 3 and higher. METHODS: This retrospective trial was conducted between January 2017 and December 2019 and included 52 patients with a CAD-RADS score of 3 and higher. Two reading sessions were performed 6 weeks apart. The first reading session was performed using only conventional images and the second reading session was performed using spectral results. Detector-based spectral CT CAD-RADS scores were compared with cardiac stress test and/or cardiac catheterization results for final characterization of stenosis in 41 segments from 32 patients. The mean CAD-RADS score was calculated for both the conventional images and spectral images. RESULTS: The CAD-RADS score for SECT and the score for spectral CT for the 41 segments were compared. Available associated stress test and/or cardiac catheterization results were also compared with CAD-RADS scores. In 51% (21/41), a diagnosis concordant with best practices results was achieved with the help of spectral CT results. A mean CAD-RADS score of 3.56 was obtained using spectral results, compared with 3.93 using conventional images. A 2-tailed paired t test determined the difference to be significant with a P value of 0.007. CONCLUSIONS: Computed tomography coronary angiography is feasible on a detector-based spectral CT scanner and can improve diagnostic confidence over SECT angiography in patients with an original CAD-RADS score of 3 and higher.

Synthetic applications of hydride abstraction reactions by organic oxidants.

Carbon-hydrogen bond functionalizations provide an attractive method for streamlining organic synthesis, and many strategies have been developed for conducting these transformations. Hydride-abstracting reactions have emerged as extremely effective methods for oxidative bond-forming processes due to their mild reaction conditions and high chemoselectivity. This review will predominantly focus on the mechanism, reaction development, natural product synthesis applications, approaches to catalysis, and use in enantioselective processes for hydride abstractions by quinone, oxoammonium ion, and carbocation oxidants. These are the most commonly employed hydride-abstracting agents, but recent efforts illustrate the potential for weaker ketone and triaryl borane oxidants, which will be covered at the end of the review.

HLA-B*07:02 and HLA-C*07:02 are associated with trimethoprim-sulfamethoxazole respiratory failure.

We have identified an underrecognized severe adverse drug reaction (ADR) of trimethoprim-sulfamethoxazole (TMP-SMX) associated respiratory failure in previously healthy children and young adults. We investigated potential genetic risk factors associated with TMP-SMX induced respiratory failure in a cohort of seven patients. We explored whole genome sequence among seven patients representing nearly half of all reported cases worldwide and 63 unrelated control individuals in two stages: (1) human leukocyte antigen (HLA) locus variation as several other ADRs have been associated HLA genetic variants and (2) coding variation to catalog and explore potential rare variants contributing to this devastating reaction. All cases were either heterozygous (carriers) or homozygous for the common HLA-B*07:02-HLA-C*07:02 haplotype. Despite the small sample size, this observation is statistically significant both in conservative comparison to maximum reported population frequencies (binomial P = 0.00017 for HLA-B and P = 0.00028 for HLA-C) and to our control population assessed by same HLA genotyping approach (binomial P = 0.000001 for HLA-B and P = 0.000018 for HLA-C). No gene elsewhere in the genome harnessed shared rare case enriched coding variation. Our results suggests that HLA-B*07:02 and HLA-C*07:02 are necessary for a patient to develop respiratory failure due to TMP-SMX.

Simulation-Based System Analysis: Testing Preparedness for Extracorporeal Membrane Oxygenation Cannulation in Pediatric COVID-19 Patients.

INTRODUCTION: Coronavirus Disease-2019 presents risk to both patients and medical teams. Staff-intensive, complex procedures such as extracorporeal membrane oxygenation (ECMO) or extracorporeal cardiopulmonary resuscitation (eCPR) may increase chances of exposure and spread. This investigation aimed to rapidly deploy an in situ Simulation-based Clinical Systems Testing (SbCST) framework to identify Latent Safety Threats (LSTs) related to ECMO/eCPR initiation during a pandemic. METHODS: The adapted SbCST framework tested systems related to ECMO/eCPR initiation in the Neonatal and Pediatric Intensive Care Units. Systems were evaluated in six domains (Resources, Processes/Systems, Facilities, Clinical Performance, Infection Control, and Communication). We conducted three high-fidelity simulations with members from the Neonatal Intensive Care Unit General Surgery, Pediatric Intensive Care Unit Cardiovascular Surgery (CV), and Pediatric Intensive Care Unit General Surgery teams. Content experts evaluated systems issues during simulation, and LSTs were identified during debriefing. Data were analyzed for frequency of LSTs and trends in process gaps. RESULTS: Sixty-six LSTs were identified across three scenarios. Resource issues comprised the largest category (26%), followed by Process/System issues (24%), Infection Control issues (24%), Communication issues (17%), and Facility and Clinical Performance issues (5% each). LSTs informed new team strategies such as the use of a "door/PPE monitor" and "inside/outside" team configuration. CONCLUSIONS: The adapted SbCST framework identified multiple LSTs related to ECMO/eCPR cannulation and infection control guidelines in the setting of Coronavirus Disease-2019. Through SbCSTs, we developed guidelines to conserve PPE and develop optimal workflows to reduce patient/staff exposure in a high-risk procedure. This project may guide other hospitals to adapt SbCSTs strategies to test/adjust rapidly changing guidelines.

Mechanism-Based Approach to Reagent Selection for Oxidative Carbon-Hydrogen Bond Cleavage Reactions.

Numerous hydride-abstracting agents generate the same cationic intermediate, but substrate features such as intermediate cation stability, oxidation potential, and steric environment can influence reaction rates in an oxidant-dependent manner. This manuscript provides experimental data to illustrate the role that structural features play in the kinetics of hydride abstraction reactions with commonly used quinone-, oxoammonium ion-, and carbocation- based oxidants. Computational studies of the transition state structures and energies explain these results and energy decomposition analysis calculations reveal unique sensitivities to electrostatic attraction and steric repulsions. Rigorous rate studies of select reactions validated the capacity of the calculations to predict reactivity trends. Additionally, kinetics studies demonstrate the potential for product inhibition in DDQ-mediated reactions. These studies provide a clear guide to select the optimal oxidant for structurally disparate substrates and lead to predictions of reactivity that were validated experimentally.

Qualitative Examination of Shared Decision-Making in Canada's Largest Health System: More Work to be Done : Shared Decision-Making-More Work to be Done.

Background: Shared Decision-Making (SDM) is an inclusive approach where patients and providers work in partnership to make health care decisions that are grounded in clinical best practice and align with patient preferences and values. Despite a growing recognition that SDM can lead to improved outcomes and reductions in unnecessary health investigations, tensions exist between patient agency and a historically paternalistic model of health care. As an evolving ideology, the Research Team sought to better understand the current state, challenges, and implementation opportunities of SDM practices across the health system. Methods: This study used a cross-sectional quality improvement design utilizing semistructured interviews to gather information from focus group participants. Five open-ended, qualitative questions were used to generate discussion on the perceptions of SDM and its role in clinical appropriateness in a variety of clinical contexts in our health system. A total of 12 focus groups (n = 95 participants) representative of patients and families, leaders, physicians, and frontline clinicians were engaged in the study. Results: Through a consensus-based approach, study results identified 4 recommendations based on 4 themes: Time, Communication, System Design, and Clinical Appropriateness. Conclusion: There are no easy solutions to the challenges of enabling SDM; however, success will be dependent upon recognizing the importance of patient agency, while maintaining an inclusive and continuous stakeholder engagement with both patients and providers. Implementation of the 4 recommendations at the organizational level highlighted in this study can serve as a road map for other health care institutions and will require a gradual approach to transform the general principles of SDM into tangible solutions to meet the emerging needs at both the local and system level.

Pneumatosis intestinalis and intestinal perforation in a case of multisystem inflammatory syndrome in children.

This case demonstrates pneumatosis intestinalis and small bowel perforation in a paediatric patient with multisystem inflammatory syndrome in children (MIS-C). Our patient presented with fever, abdominal pain and shortness of breath. She progressed to haemodynamic failure and small bowel perforation approximately 1 week after admission. Patients with suspected or confirmed MIS-C should be monitored closely for abdominal catastrophe, especially when critically ill in the intensive care unit.

Variation in acute fluid resuscitation among pediatric burn centers.

BACKGROUND: Accurate resuscitation of pediatric patients with large thermal injury is critical to achieving optimal outcomes. The goal of this project was to describe the degree of variability in resuscitation guidelines among pediatric burn centers and the impact on fluid estimates. METHODS: Five pediatric burn centers in the Pediatric Injury Quality Improvement Collaborative (PIQIC) contributed data from patients with ≥15% total body surface area (TBSA) burns treated from 2014 to 2018. Each center's resuscitation guidelines and guidelines from the American Burn Association were used to calculate estimated 24-h fluid requirements and compare these values to the actual fluid received. RESULTS: Differences in the TBSA burn at which fluid resuscitation was initiated, coefficients related to the Parkland formula, criteria to initiate dextrose containing fluids, and urine output goals were observed. Three of the five centers' resuscitation guidelines produced statistically significant lower mean fluid estimates when compared with the actual mean fluid received for all patients across centers (4.53 versus 6.35ml/kg/% TBSA, p<0.001), (4.90 versus 6.35ml/kg/TBSA, p=0.002) and (3.38 versus 6.35ml/kg/TBSA, p<0.0001). CONCLUSIONS: This variation in practice patterns led to statistically significant differences in fluid estimates. One center chose to modify its resuscitation guidelines at the conclusion of this study.

Implementation and Maintenance of a Pediatric Severe Burn Guidelines Quality Improvement Project.

Introduction: Critically injured pediatric burn patients require specialized management, yet few verified pediatric burn centers exist in the United States. Many pediatric hospitals have resources to care for severely burned patients but lack standardized care guidelines, which improve outcomes. To improve the morbidity and mortality of severely burned pediatric patients admitted to the pediatric intensive care unit, we created a specialized burn team. We implemented Pediatric Severe Burn Guidelines, focusing on improving fluid resuscitation accuracy and providing timely nutritional support. Methods: This investigation is of a 9-year (2010-2019) retrospective preintervention and postintervention study of the effect of the formation of a multidisciplinary burn leadership committee and development and implementation of Pediatric Severe Burn Guidelines. The primary outcome measures are increasing the accuracy of fluid resuscitation and improving the timely administration of nutritional support. The process measure is the percentage of time the electronic health record power plan was used for burn admissions with burn leadership review of the cases. Balancing measures are pediatric intensive care unit and hospital length of stay. Results: Preprotocol patients received acceptable fluid resuscitation 25% (5/20) of the time compared to 61.5% (8/13) of the time in postprotocol patients (P = 0.04). In postprotocol patients, there is an improvement in the timely placement of postpyloric feeding tube and initiation of feeds 48 hours after admission. Conclusions: Extensive guidelines for standardized care require careful implementation and monitoring of adherence gaps. Creating a specialized burn team and implementing clinical guidelines standardize care leading to improvement in critical patient outcomes.

Soy-tomato enriched diet reduces inflammation and disease severity in a pre-clinical model of chronic pancreatitis.

Chronic pancreatitis (CP) is a fibro-inflammatory syndrome in individuals who develop persistent pathological responses to parenchymal injury or stress. Novel therapeutic or dietary interventions that could lessen inflammation in this disease could significantly improve quality of life in patients with CP. Complex dietary foods like soy and tomatoes are composed of active metabolites with anti-inflammatory effects. Data from our group reports that bioactive agents in soy and tomatoes can reduce pro-inflammatory cytokines and suppressive immune populations. Additionally, our team has developed a novel soy-tomato juice currently being studied in healthy individuals with no toxicities, and good compliance and bioavailability. Thus, we hypothesize that administration of a soy-tomato enriched diet can reduce inflammation and severity of CP. C57BL/6 mice were injected intraperitoneally with 50 µg/kg caeurlein (7 hourly injections, twice weekly) for 6 weeks to induce CP. After 4 weeks of caerulein injections, mice were administered a control or a soy-tomato enriched diet for 2 weeks. Disease severity was measured via immunohistochemical analysis of pancreata measuring loss of acini, fibrosis, inflammation, and necrosis. Serum lipase and amylase levels were analyzed at the end of the study. Inflammatory factors in the serum and pancreas, and immune populations in the spleen of mice were analyzed by cytokine multiplex detection, qRT-PCR, and flow cytometry respectively. Infra-red (IR) sensing of mice was used to monitor spontaneous activity and distress of mice. Mice fed a soy-tomato enriched diet had a significantly reduced level of inflammation and severity of CP (p = 0.032) compared to mice administered a control diet with restored serum lipase and amylase levels (p < 0.05). Mice with CP fed a soy-tomato diet had a reduction in inflammatory factors (TNF-α, IL-1ß, IL-5) and suppressive immune populations (myeloid-derived suppressor cells; MDSC) compared to control diet fed mice (p < 0.05). Infra-red sensing to monitor spontaneous activity of mice showed that soy-tomato enriched diet improved total activity and overall health of mice with CP (p = 0.055) and CP mice on a control diet were determined to spend more time at rest (p = 0.053). These pre-clinical results indicate that a soy-tomato enriched diet may be a novel treatment approach to reduce inflammation and pain in patients with CP.

Extracorporeal Membrane Oxygenation as a Bridge to Chimeric Antigen Receptor T-cell Therapy for Severe Refractory Sepsis in the Setting of Relapsed Refractory Pediatric Acute Lymphoblastic Leukemia: A Case Report.

Pediatric oncology patients with sepsis are at higher risk of morbidity and mortality compared with pediatric patients without malignancy. Historically, patients with relapsed and/or refractory disease were not considered candidates for aggressive life support strategies including extracorporeal membrane oxygenation support. CASE SUMMARY: We report a 4-year-old female with relapsed refractory pre-B cell acute lymphoblastic leukemia preparing for chimeric antigen receptor T cell therapy with tisagenlecleucel who was admitted with fever and neutropenia. She progressed to refractory septic shock secondary to Escherichia coli bacteremia and required escalation of hemodynamic support to venoarterial extracorporeal membrane oxygenation cannulation. She cleared her E. coli bacteremia, was decannulated, subsequently received her chimeric antigen receptor T-cell therapy, and was declared disease free 1 month from her initial presentation. CONCLUSION: The ability to provide chimeric antigen receptor T-cell therapy at designated institutions can augment extracorporeal membrane oxygenation candidacy discussions in oncology patients with relapsed disease and may make extracorporeal membrane oxygenation candidacy for oncology patients with refractory sepsis more favorable.

Pharmacogenomics of Pain Management: The Impact of Specific Biological Polymorphisms on Drugs and Metabolism.

PURPOSE OF REVIEW: Pain is multifactorial and complex, often with a genetic component. Pharmacogenomics is a relative new field, which allows for the development of a truly unique and personalized therapeutic approach in the treatment of pain. RECENT FINDINGS: Until recently, drug mechanisms in humans were determined by testing that drug in a population and calculating response averages. However, some patients will inevitably fall outside of those averages, and it is nearly impossible to predict who those outliers might be. Pharmacogenetics considers a patient's unique genetic information and allows for anticipation of that individual's response to medication. Pharmacogenomic testing is steadily making progress in the management of pain by being able to identify individual differences in the perception of pain and susceptibility and sensitivity to drugs based on genetic markers. This has a huge potential to increase efficacy and reduce the incidence of iatrogenic drug dependence and addiction. The streamlining of relevant polymorphisms of genes encoding receptors, transporters, and drug-metabolizing enzymes influencing the pain phenotype can be an important guide to develop safe new strategies and approaches to personalized pain management. Additionally, some challenges still prevail and preclude adoption of pharmacogenomic testing universally. These include lack of knowledge about pharmacogenomic testing, inadequate standardization of the process of data handling, questionable benefits about the clinical and financial aspects of pharmacogenomic testing-guided therapy, discrepancies in clinical evidence supporting these tests, and doubtful reimbursement of the tests by health insurance agencies.

Severe Acute Respiratory Failure in Healthy Adolescents Exposed to Trimethoprim-Sulfamethoxazole.

Pulmonary toxicity induced by trimethoprim-sulfamethoxazole (TMP-SMX) has been described, although the disease process is poorly understood. We report 5 previously healthy adolescent patients who developed acute respiratory failure while taking TMP-SMX. Four of the 5 adolescents required extracorporeal membrane oxygenation support, and 2 of the teenagers died. All children required a tracheostomy, and all cases were complicated by pneumothoraces and pneumomediastinum. The majority of children were prescribed TMP-SMX for the treatment of acne vulgaris.