The oral microbiota and periodontal health in orthodontic patients.

The oral microbiota develops within the first 2 years of childhood and becomes distinct from the parents by 4 years-of-age. The oral microbiota plays an important role in the overall health/symbiosis of the individual. Deviations from the state of symbiosis leads to dysbiosis and an increased risk of pathogenicity. Deviations can occur not only from daily life activities but also from orthodontic interventions. Orthodontic appliances are formed from a variety of biomaterials. Once inserted, they serve as a breeding ground for microbial attachment, not only from new surface areas and crevices but also from material physicochemical interactions different than in the symbiotic state. Individuals undergoing orthodontic treatment show, compared with untreated people, qualitative and quantitative differences in activity within the oral microbiota, induced by increased retention of supra- and subgingival microbial plaque throughout the treatment period. These changes are at the root of the main undesirable effects, such as gingivitis, white spot lesions (WSL), and more severe caries lesions. Notably, the oral microbiota profile in the first weeks of orthodontic intervention might be a valuable indicator to predict and identify higher-risk individuals with respect to periodontal health and caries risk within an otherwise healthy population. Antimicrobial coatings have been used to dissuade microbes from adhering to the biomaterial; however, they disrupt the host microbiota, and several bacterial strains have become resistant. Smart biomaterials that can reduce the antimicrobial load preventing microbial adhesion to orthodontic appliances have shown promising results, but their complexity has kept many solutions from reaching the clinic. 3D printing technology provides opportunities for complex chemical syntheses to be performed uniformly, reducing the cost of producing smart biomaterials giving hope that they may reach the clinic in the near future. The purpose of this review is to emphasize the importance of the oral microbiota during orthodontic therapy and to use innovative technologies to better maintain its healthy balance during surgical procedures.

qPCR assay for detection of Woodchuck Hepatitis Virus Post-Transcriptional Regulatory Elements from CAR-T and TCR-T cells in fresh and formalin-fixed tissue.

As adoptive cellular therapies become more commonplace in cancer care, there is a growing need to monitor site-specific localization of engineered cells-such as chimeric antigen receptor T (CAR-T) cells and T-cell receptor T (TCR-T) cells-in patients' tissues to understand treatment effectiveness as well as associated adverse events. Manufacturing CAR-T and TCR-T cells involves transduction with viral vectors commonly containing the WPRE gene sequence to enhance gene expression, providing a viable assay target unique to these engineered cells. Quantitative PCR (qPCR) is currently used clinically in fresh patient tissue samples and blood with target sequences specific to each immunotherapy product. Herein, we developed a WPRE-targeted qPCR assay that is broadly applicable for detection of engineered cell products in both fresh and archival formalin-fixed paraffin embedded (FFPE) tissues. Using both traditional PCR and SYBR Green PCR protocols, we demonstrate the use of this WPRE-targeted assay to successfully detect two CAR-T cell and two TCR-T cell products in FFPE tissue. Standard curve analysis reported a reproducible limit of detection at 100 WPRE copies per 20µL PCR reaction. This novel and inexpensive technique could provide better understanding of tissue abundance of engineered therapeutic T cells in both tumor and second-site toxicity tissues and provide quantitative assessment of immune effector cell trafficking in archival tissue.

Safety and Efficacy of In-Office Hand Procedures.

Background: The primary concerns with operating on patients in the office setting are insufficient sterility and lack of appropriate resources in case of excessive bleeding or other surgical complications. This study serves to investigate these concerns and determine whether in-office hand surgeries are safe and clinically effective. Methods: A retrospective review of patients who underwent minor hand operations in the office setting between December 2020 and December 2021 was performed. The surgical procedures included in this analysis are needle aponeurotomy, trigger finger release, foreign body removal, mass removal, and reduction in a finger fracture with or without percutaneous pinning. All fractures, which primarily included metacarpal and phalangeal fractures, were subsequently splinted. Sterility and hemostatic support were achieved via the Wide-Awake Local Anesthesia No Tourniquet (WALANT) method. Major complications were defined as infection, major bleeding, and neurological deficits. Minor complications were defined as prolonged pain, prolonged inflammation, residual symptoms, and recurrence of symptoms within 1 month. Results: Five patients (3.8%) returned to the office for pain, inflammation, or stiffness of the affected finger, with two of the five returning with symptoms associated with osteoarthritis or pseudogout flare-ups. Five additional patients returned due to residual symptoms or recurrence of the primary complaint within 1 month of surgery. No patients experienced exogenous infection. Conclusion: The absence of major complications and high success rate for minor hand procedures shows the high degree of safety and efficacy that can be achieved via the in-office setting for select procedures. While proper patient selection is key, our result shows the in-office procedure room setting can offer the necessary elements of sterility and hemostatic support for several common hand surgeries.

Nano-architectonics of Pt single-atoms and differently-sized nanoparticles supported by manganese-oxide nanosheets and impact on catalytic and anti-biofilm activities.

Hybrid-nanozymes are promising in various applications, but comprehensive comparison of hybrid-nanozymes composed of single-atoms or nanoparticles on the same support has never been made. Here, manganese-oxide nanosheets were loaded with Pt-single-atoms or differently-sized nanoparticles and their oxidase- and-peroxidase activities compared. High-resolution Transmission-Electron-Microscopy and corresponding Fast Fourier Transform imaging showed that Pt-nanoparticles (1.5 nm diameter) had no clear (111) crystal-planes, while larger nanoparticles had clear (111) crystal-planes. X-ray Photo-electron Spectroscopy demonstrated that unloaded nanosheets were composed of MnO2 with a high number of oxygen vacancies (Vo/Mn 0.4). Loading with 7.0 nm Pt-nanoparticles induced a change to Mn2O3, while loading with 1.5 nm nanoparticles increased the number of vacancies (Vo/Mn 1.2). Nanosheets loaded with 3.0 nm Pt-nanoparticles possessed similarly high catalytic activities as Pt-single-atoms. However, loading with 1.5 nm or 7.0 nm Pt-nanoparticles yielded lower catalytic activities. A model is proposed explaining the low catalytic activity of under- and over-sized Pt-nanoparticles as compared with intermediately-sized (3.0 nm) Pt-nanoparticles and single-atoms. Herewith, catalytic activities of hybrid-nanozymes composed of single-atoms and intermediately-sized nanoparticles are put a par, as confirmed here with respect to bacterial biofilm eradication. This conclusion facilitates a balanced choice between using Pt-single-atoms or nanoparticles in further development and application of hybrid-nanozymes.

Skin integrity preservation using a nurse-constructed silicone adhesive Foley catheter.

AIMS: Skin breakdown is common in the intensive care unit (ICU). This pilot evaluation aimed to determine whether a nurse-constructed urinary catheter securement device using a silicone adhesive could reduce the complications of blistering and other skin breakdowns in a high-risk ICU population with Foley catheters. DESIGN: A prospective, non-randomised performance improvement study using a convenience sample was carried out. SUBJECTS AND SETTING: The study sample consisted of 29 patients with urethral Foley catheters and any degree of thigh oedema in a surgical ICU at an academic quarternary medical center. METHODS: Patients were fitted with a standard acrylic-adhesive catheter securement device on one thigh and a nurse-constructed device on the contralateral thigh. At the beginning of each 12-hour shift, the nurse moved the Foley catheter from one securement device to the other; the nurse recorded the assessment findings at the end of the shift. RESULTS: The average age of the 29 patients was 61±16 (range 20-87) years. Visible skin compromise occurred in 21% of the time with the standard acrylic securement device; an equal percentage of men and women developed skin breakdown. Oedema status was a significant factor related to skin breakdown. There was no visible damage to the skin associated with the nurse-constructed silicone-adhesive device. CONCLUSIONS: A silicone adhesive urinary catheter securement device causes less skin damage than one with acrylic adhesive. One-step application, pain-free and atraumatic removal, and reliable securement are essential considerations in product development.

Social support for young people with eating disorders-An integrative review.

Eating disorder treatment should be underpinned by a recovery-oriented approach, be therapeutic, personalised and trauma informed. Within such models of care, social support is an important factor to explore in terms of its influence in supporting hope for recovery, reducing stigma, and mitigating life stressors. Limited research has been conducted to understand the types of social support that are available to young people formally diagnosed with an eating disorder, their feasibility and acceptability and the positive outcomes. This integrative review sought to explore the positive outcomes of social support or social support programs for young people with eating disorders. An integrative review was conducted based on a search of five electronic databases from inception to 31 March 2023. Methodological quality was assessed using the Joanna Briggs Institute Critical Appraisal Tools and findings have been narratively synthesised and presented in accordance with the review's aims and questions. Seven studies (total 429 individuals, range 3-160) published between 2001 and 2023 were included in the final synthesis. Overall social support interventions showed promising preliminary evidence as a feasible and acceptable adjunct to treatment for young people with an eating disorder motivated to change, with some clinical improvements in psychopathology. Social support augmented existing relationships, providing a human element of open dialogue, friendship and a sense of hope for recovery. Despite the small number and heterogeneity of the studies, this review has highlighted some promising preliminary benefits. Future treatment for eating disorders should embrace adjunct modalities that enhance psychosocial recovery for young people with eating disorders.

Prognostic and morphological factors in pediatric cerebellar contusions.

Background: Although uncommon, cerebellar contusions are associated with significant morbidity and mortality. Literature is lacking in the prognostic and morphological factors relating to their clinical picture and outcomes, especially within children. The objective of this study is to evaluate prognostic and anatomic factors in the clinical picture of cerebellar contusions, including effacement of the 4th ventricle and cisterna magna. Methods: This is a retrospective chart review over 11 years across two medical centers. Patients included were under 18 years who presented with a cerebellar contusion. Patients were stratified within the study group based on discharge Glasgow outcome scale (GOS) and reviewed for prognostic factors contributing to outcome. Mid sagittal area of the 4th ventricle and cisterna magna were measured using magnetic resonance imaging and compared within the groups. Results: A total of 21 patients met the study criteria, of which 16 (76.2%) were male, with an average patient age of 8.65 years. Poor outcome at discharge (GOS <4) was associated with decreased admission Glasgow coma scale (P = 0.003), admission motor response (P = 0.006), pupil reactivity (P = 0.014), presence of concomitant subarachnoid hemorrhage (P = 0.010), contusion volume (P < 0.001), and decreased area of the cisterna magna (P = 0.012). Patients with poor outcomes were also more likely to require surgical intervention (P = 0.042). Conclusion: There are multiple prognostic factors associated with the overall outcome following cerebellar contusions. The rate of good outcomes in this study was superior to that in previous studies in adults.

Sleep disorder risk, perceived control over sleep, and mental health symptoms in paramedicine students.

Paramedics commonly experience both poor sleep and mental health symptoms. Clarifying whether sleep or mental health symptoms are a challenge prior to commencement of employment is important, as early prevention and intervention initiatives during training could support these workers. Paramedicine students (n=53) were included, with sleep disorder screening (obstructive sleep apnea, insomnia and restless legs syndrome), and mental health outcomes (depressive symptoms: Patient Health Questionnaire-9, and anxiety symptoms: General Anxiety Disorder-7). Data were analysed using robust regression models, adjusted for age, sex, and shift work status. Meeting criteria for a sleep disorder (n=21) was associated with higher scores for anxiety (8.2 [95% CI: 5.9-10.5] v 4.6, [3.4-5.8]) and depressive symptoms (11.1 [8.6-13.6] v 4.4 [3.1-5.7)] compared to those who did not meet the criteria for a sleep disorder (n=32). Depressive symptoms were lower in those with perceived control over sleep (5.2 [3.2-7.2] v 9.8 [7.7-11.8]). There was no interaction between sleep disorder risk and perceived control over sleep on mental health symptoms. Investigation and management of factors contributing to low perceived control over sleep, together with early screening and management of sleep disorders, are likely to be important priorities to support paramedic student wellbeing prior to commencing shift work.

Unconstrained Precision Mitochondrial Genome Editing with αDdCBEs.

DddA-derived cytosine base editors (DdCBEs) enable the targeted introduction of C•G-to-T•A conversions in mitochondrial DNA (mtDNA). DdCBEs are often deployed as pairs, with each arm comprised of a transcription activator-like effector (TALE), a split double-stranded DNA deaminase half, and a uracil glycosylase inhibitor. This pioneering technology has helped improve our understanding of cellular processes involving mtDNA and has paved the way for the development of models and therapies for genetic disorders caused by pathogenic mtDNA variants. Nonetheless, given the intrinsic properties of TALE proteins, several target sites in human mtDNA remain out of reach to DdCBEs and other TALE-based technologies. Specifically, due to the conventional requirement for a thymine immediately upstream of the TALE target sequences (i.e., the 5'-T constraint), over 150 loci in the human mitochondrial genome are presumed to be inaccessible to DdCBEs. Previous attempts at circumventing this constraint, either by developing monomeric DdCBEs or utilizing DNA-binding domains alternative to TALEs, have resulted in suboptimal specificity profiles with reduced therapeutic potential. Here, aiming to challenge and elucidate the relevance of the 5'-T constraint in the context of DdCBE-mediated mtDNA editing, and to expand the range of motifs that are editable by this technology, we generated αDdCBEs that contain modified TALE proteins engineered to recognize all 5' bases. Notably, 5'-T-noncompliant, canonical DdCBEs efficiently edited mtDNA at diverse loci. However, DdCBEs were frequently outperformed by αDdCBEs, which consistently displayed significant improvements in activity and specificity, regardless of the 5'-most bases of their TALE binding sites. Furthermore, we showed that αDdCBEs are compatible with DddA tox and its derivatives DddA6, and DddA11, and we validated TALE shifting with αDdCBEs as an effective approach to optimize base editing outcomes at a single target site. Overall, αDdCBEs enable efficient, specific, and unconstrained mitochondrial base editing.

An Unusual Presentation of Adult Intussusception.

Intussusception is a condition characterized by the invagination of a proximal segment of the intestine into a distal segment. In adults, intussusception is commonly associated with a lead point. The most alarming lead point is an obstructing malignancy. Here, we present the case of a 57-year-old woman with ileocolic intussusception secondary to colonic adenocarcinoma. The patient presented to the emergency department following an incidental finding of bradycardia, with a heart rate of around 40 beats per minute. She presented with several weeks of cramping, right lower quadrant abdominal pain, lightheadedness, fatigue, and palpitations. A computed tomography scan revealed ileocolic intussusception. After the placement of a semi-permanent right subclavian pacer, the patient underwent a right hemicolectomy. Surgical findings were consistent with ileocolic intussusception suspicious of being initiated by a mass in the right cecum involving the appendiceal orifice and ileocecal valve that invaded through the muscularis propria into subserosal tissue. The mass was resected and sent to pathology, where it was classified as stage II colonic adenocarcinoma. This case highlights a nonspecific presentation of intussusception that was only identified due to incidental bradycardia.

Chemical Pleurodesis in the Treatment of Recurrent Chylothorax Due to Renal Cell Carcinoma.

Chylothorax is defined as a pleural effusion with triglyceride levels greater than 110 mg/dL and/or chylomicrons present in the pleural fluid. A chylothorax may be classified as traumatic or nontraumatic, with malignancy being the most common cause of atraumatic chylothoraces. Herein, we present the case of a 63-year-old woman with a past medical history of a mediastinal teratoma and stage III colon adenocarcinoma who presented to the emergency room with new-onset shortness of breath. A week prior to presentation, she was diagnosed with metastatic renal cell carcinoma after a retrocrural lymph node was biopsied. In the emergency department, a chest X-ray revealed a large right-sided pleural effusion, which was later diagnosed as a chylothorax based on pleural fluid analysis. Thoracentesis was performed and the patient was sent home. Three days later, the patient returned after experiencing palpitations and shortness of breath. The patient was diagnosed with recurrent chylothorax after a repeat chest X-ray and thoracentesis. The patient was ultimately treated with chemical pleurodesis. To the best of our knowledge, this case is the only reported chylothorax due to renal cell carcinoma metastasis reported in the literature. It describes the presentation and subsequent successful treatment of this rare condition with chemical pleurodesis.

Enzalutamide: Understanding and Managing Drug Interactions to Improve Patient Safety and Drug Efficacy.

Enzalutamide is an oral androgen receptor signaling inhibitor utilized in the treatment of men with prostate cancer. It is a moderate inducer of the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C19, and a strong inducer of CYP3A4. It was also shown to be a mild inhibitor of the efflux transporter P-glycoprotein in patients with prostate cancer. Enzalutamide is primarily metabolized by CYP3A4 and CYP2C8. The risk of enzalutamide drug interactions arises primarily when it is coadministered with other drugs that interact with these CYPs, including CYP3A4. In this review, we begin by providing an overview of enzalutamide including its dosing, use in special populations, pharmacokinetics, changes to its prescribing information, and potential for interaction with coadministered drugs. Enzalutamide interactions with drugs from a wide range of medication classes commonly prescribed to patients with prostate cancer are described, including oral androgen deprivation therapy, agents used to treat a range of cardiovascular diseases, antidiabetic drugs, antidepressants, anti-seizure medications, common urology medications, analgesics, proton pump inhibitors, immunosuppressants, and antigout drugs. Enzalutamide interactions with common vitamins and supplements are also briefly discussed. This review provides a resource for healthcare practitioners and patients that will help provide a basis for the understanding and management of enzalutamide drug-drug interactions to inform decision making, improve patient safety, and optimize drug efficacy.

Enzalutamide is a drug that is used to treat various stages of advanced prostate cancer, a type of cancer that begins in the prostate and may spread beyond the prostate. Enzalutamide stops testosterone from stimulating prostate cancer growth. Like other drugs, enzalutamide enters the bloodstream, and then is processed and removed from the body. Sometimes, when a person takes multiple drugs, one drug can make it difficult for the body to process and remove one or more of the other drugs. This is referred to as a drug interaction. Enzalutamide drug interactions can cause the level of other drugs in the body to increase or decrease in an abnormal way. It is also possible for certain other drugs to alter the levels of enzalutamide. Drug interactions that cause the level of a drug to get too low can prevent that drug from working effectively, whereas drug interactions that cause the level of a drug to get too high can lead to side effects of that drug. People with prostate cancer are mostly aged 65 years or older and often take medications to treat a variety of diseases. Examples include medications to treat heart conditions, diabetes, high cholesterol, high blood pressure, and many other conditions. Here, we describe enzalutamide drug interactions with these types of medications. Our goal is to provide a resource to help healthcare providers and patients better understand enzalutamide drug interactions and how to manage them to improve patient safety and drug effectiveness.

Left ventricular shape index and eccentricity index with ECG-gated Nitrogen-13 ammonia PET/CT in patients with myocardial infarction, ischemia, and normal perfusion.

BACKGROUND: LV geometry with shape index (SI) and eccentricity index (EI) measured by myocardial perfusion positron emission tomography/computed tomography (PET/CT) may allow the evaluation of left ventricular (LV) adverse remodeling. This first study aims to explore the relationship of SI and EI values acquired by Nitrogen-13 ammonia PET/CT in patients with normal perfusion, ischemia, and myocardial infarction. And evaluate the correlations between the variables of LV geometry, and with the variables of LV function. METHODS AND RESULTS: One hundred and forty patients who underwent an electrocardiogram (ECG)-gated PET/CT were selected and classified into 4 groups according to ischemia or infarction burden (normal perfusion, mild ischemia, moderate-severe ischemia, and infarction). The variables were automatically retrieved using dedicated software (QPS/QGS; Cedars-Sinai, Los Angeles, CA, USA). On multicomparison analysis (one-way ANOVA and Dunnett's Test), subjects in the infarction group had significant higher values of SI end-diastolic rest (P < 0.001), and stress (P = 0.003), SI end-systolic rest (P = 0.002) and stress (P < 0.001) as well as statistically significant lower values of EI rest (P < 0.001) and stress (P < 0.001) when compared with all other groups. Regarding Pearson correlation, in the infarcted group all the variables of SI and EI were significantly correlated (P < 0.001) with strong correlation coefficients (>0.60). SI end-systolic correlated significantly with the variables of LV function independently of the group of patients (P < 0.05). CONCLUSIONS: Shape and eccentricity indices differ in patients with myocardial infarction as compared to patients with ischemia or normal perfusion. This encourage further research in their potential for detecting LV adverse remodeling.

Dynamic "spiked helmet sign": Further evidence for prolonged QT.

A 69-year-old woman was admitted after a cardiac arrest. She developed status epilepticus and was later found to have variable morphologies of a "spiked helmet sign" (SHS) on ECGs in the setting of prolonged QT interval, raising the question of whether this sign is a manifestation of QT prolongation.

Attending to the complexities of leadership learning and practice: Emergent-based assessment and evaluation strategies.

In emergence-based leadership education, the knowledge and experiences co-created in the classroom may violate some of the assumptions behind traditional teaching and learning assessment methods. Thus, traditional assessment, evaluation, and outcomes for courses utilizing emergence-based methods, such as intentional emergence, case-in-point, dialogic group process consultations, and group relations/dynamics, are counterintuitive and must be reconsidered. We provide recommendations regarding how to conduct assessment when utilizing emergence-based teaching methods in leadership education. We review the use of inductive forms of assessment and provide recommendations for broadening learning outcomes and engaging in learning outcomes beyond the knowledge domain.

The degree of aortic occlusion in the setting of trauma alters the extent of acute kidney injury associated with mitochondrial preservation.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is used to control noncompressible hemorrhage not addressed with traditional tourniquets. However, REBOA is associated with acute kidney injury (AKI) and subsequent mortality in severely injured trauma patients. Here, we investigated how the degree of aortic occlusion altered the extent of AKI in a porcine model. Female Yorkshire-cross swine (n = 16, 68.1 ± 0.7 kg) were anesthetized and had carotid and bilateral femoral arteries accessed for REBOA insertion and distal and proximal blood pressure monitoring. Through a laparotomy, a 6-cm liver laceration was performed and balloon inflation was performed in zone 1 of the aorta for 90 min, during which animals were randomized to target distal mean arterial pressures of 25 or 45 mmHg via balloon volume adjustment. Blood draws were taken at baseline, end of occlusion, and time of death, at which point renal tissues were harvested 6 h after balloon deflation for histological and molecular analyses. Renal blood flow was lower in the 25-mmHg group (48.5 ± 18.3 mL/min) than in the 45-mmHg group (177.9 ± 27.2 mL/min) during the occlusion phase, which recovered and was not different after balloon deflation. AKI was more severe in the 25-mmHg group, as evidenced by circulating creatinine, blood urea nitrogen, and urinary neutrophil gelatinase-associated lipocalin. The 25-mmHg group had increased tubular necrosis, lower renal citrate synthase activity, increased tissue and circulating syndecan-1, and elevated systemic inflammatory cytokines. The extent of renal ischemia-induced AKI is associated with the magnitude of mitochondrial biomass and systemic inflammation, highlighting potential mechanistic targets to combine with partial REBOA strategies to prevent AKI.NEW & NOTEWORTHY Large animal models of ischemia-reperfusion acute kidney injury (IR-AKI) are lacking. This report establishes a titratable IR-AKI model in swine in which a balloon catheter can be used to alter distal pressures experienced by the kidney, thus controlling renal blood flow. Lower blood flow results in greater renal dysfunction and structural damage, as well as lower mitochondrial biomass, elevated systemic inflammation, and vascular dysfunction.

Enhanced Donor Antigen Presentation by B Cells Predicts Acute Cellular Rejection and Late Outcomes After Transplantation.

Background: Enhanced B-cell presentation of donor alloantigen relative to presentation of HLA-mismatched reference alloantigen is associated with acute cellular rejection (ACR), when expressed as a ratio called the antigen presenting index (API) in an exploratory cohort of liver and intestine transplant (LT and IT) recipients. Methods: To test clinical performance, we measured the API using the previously described 6-h assay in 84 LT and 54 IT recipients with median age 3.3 y (0.05-23.96). Recipients experiencing ACR within 60 d after testing were termed rejectors. Results: We first confirmed that B-cell uptake and presentation of alloantigen induced and thus reflected the alloresponse of T-helper cells, which were incubated without and with cytochalasin and primaquine to inhibit antigen uptake and presentation, respectively. Transplant recipients included 76 males and 62 females. Rejectors were tested at median 3.6 d before diagnosis. The API was higher among rejectors compared with nonrejectors (2.2 ±â€…0.2 versus 0.6 ±â€…0.04, P value = 1.7E-09). In logistic regression and receiver-operating-characteristic analysis, API ≥1.1 achieved sensitivity, specificity, and positive and negative predictive values for predicting ACR in 99 training set samples. Corresponding metrics ranged from 80% to 88% in 32 independent posttransplant samples, and 73% to 100% in 20 independent pretransplant samples. In time-to-event analysis, API ≥1.1 predicted higher incidence of late donor-specific anti-HLA antibodies after API measurements in LT recipients (P = 0.011) and graft loss in IT recipients (P = 0.008), compared with recipients with API <1.1, respectively. Conclusions: Enhanced donor antigen presentation by circulating B cells predicts rejection after liver or intestine transplantation as well as higher incidence of DSA and graft loss late after transplantation.

An oxidative photocyclization approach to the synthesis of Securiflustra securifrons alkaloids.

Securines and securamines are cytotoxic alkaloids that contain reactive alkene and heterocyclic residues embedded in skeletons comprising four to six oxidized rings. This structural complexity imparts a rich chemistry to the isolates but has impeded synthetic access to the structures in the nearly three decades since their isolation. We present a flexible route to eight isolates that exemplify the three skeletal classes of metabolites. The route proceeds by the modular assembly of the advanced azides 38 and 49 (13 steps, 6 to 10% yield), sequential oxidative photocyclizations, and late-stage functional group manipulations. With this approach, the targets were obtained in 17 to 19 steps, 12 to 13 purifications, and 0.5 to 3.5% overall yield. The structure of an advanced intermediate was elucidated by microcrystal electron diffraction (MicroED) analysis. The route will support structure-function and target identification studies of the securamines.

Core outcomes in nerve surgery: development of a core outcome set for brachial plexus and upper extremity nerve injuries.

OBJECTIVE: When considering traumatic brachial plexus and upper extremity nerve injuries, iatrogenic nerve injuries, and nontraumatic nerve injuries, brachial plexus and upper extremity nerve injuries are commonly encountered in clinical practice. Despite this, data synthesis and comparison of available studies are difficult. This is at least in part due to the lack of standardization in reporting and a lack of a core outcome set (COS). Thus, there is a need for a COS for adult brachial plexus and upper extremity nerve injuries (COS-BPUE). The objective of this study was to develop a COS-BPUE using a modified Delphi approach. METHODS: A 5-stage approach was used to develop the COS-BPUE: 1) consortium development, 2) literature review to identify potential outcome measures, 3) Delphi survey to develop consensus on outcomes for inclusion, 4) Delphi survey to develop definitions, and 5) consensus meeting to finalize the COS and definitions. The study followed the Core Outcome Set-STAndards for Development (COS-STAD) recommendations. RESULTS: The Core Outcomes in Nerve Surgery (COINS) Consortium comprised 23 participants, all neurological surgeons, representing 13 countries. The final COS-BPUE consisted of 36 data points/outcomes covering demographic, diagnostic, patient-reported outcome, motor/sensory outcome, and complication domains. Appropriate instruments, methods of testing, and definitions were set. The consensus minimum duration of follow-up was 24 months, with the consensus optimal time points for assessment being preoperatively and 3, 6, 12, and 24 months postoperatively. CONCLUSIONS: The COINS Consortium developed a consensus COS and provided definitions, methods of implementation, and time points for assessment. The COS-BPUE should serve as a minimum set of data that should be collected in all future neurosurgical studies on adult brachial plexus and upper extremity nerve injuries. Incorporation of this COS should help improve consistency in reporting, data synthesis, and comparability, and should minimize outcome reporting bias.

Systemically administered low-affinity HER2 CAR T cells mediate antitumor efficacy without toxicity.

BACKGROUND: The paucity of tumor-specific targets for chimeric antigen receptor (CAR) T-cell therapy of solid tumors necessitates careful preclinical evaluation of the therapeutic window for candidate antigens. Human epidermal growth factor receptor 2 (HER2) is an attractive candidate for CAR T-cell therapy in humans but has the potential for eliciting on-target off-tumor toxicity. We developed an immunocompetent tumor model of CAR T-cell therapy targeting murine HER2 (mHER2) and examined the effect of CAR affinity, T-cell dose, and lymphodepletion on safety and efficacy. METHODS: Antibodies specific for mHER2 were generated, screened for affinity and specificity, tested for immunohistochemical staining of HER2 on normal tissues, and used for HER2-targeted CAR design. CAR candidates were evaluated for T-cell surface expression and the ability to induce T-cell proliferation, cytokine production, and cytotoxicity when transduced T cells were co-cultured with mHER2+ tumor cells in vitro. Safety and efficacy of various HER2 CARs was evaluated in two tumor models and normal non-tumor-bearing mice. RESULTS: Mice express HER2 in the same epithelial tissues as humans, rendering these tissues vulnerable to recognition by systemically administered HER2 CAR T cells. CAR T cells designed with single-chain variable fragment (scFvs) that have high-affinity for HER2 infiltrated and caused toxicity to normal HER2-positive tissues but exhibited poor infiltration into tumors and antitumor activity. In contrast, CAR T cells designed with an scFv with low-affinity for HER2 infiltrated HER2-positive tumors and controlled tumor growth without toxicity. Toxicity mediated by high-affinity CAR T cells was independent of tumor burden and correlated with proliferation of CAR T cells post infusion. CONCLUSIONS: Our findings illustrate the disadvantage of high-affinity CARs for targets such as HER2 that are expressed on normal tissues. The use of low-affinity HER2 CARs can safely regress tumors identifying a potential path for therapy of solid tumors that exhibit high levels of HER2.