Brigham and Women's Hospital

Rationale ADP‐ribosylation is a posttranslational modification whose higher‐energy collisional dissociation (HCD) products are dominated by complete or partial modification losses, complicating peptide sequencing and acceptor site localization efforts. We tested whether in‐source collision‐induced dissociation (CID) performed on a quadrupole‐Orbitrap could convert ADPr to the smaller phosphoribose‐H2O derivative to facilitate HCD‐dependent peptide sequencing. Methods ADP‐ribosyl (ADPr) peptides derived from the human macrophage‐like cell line THP‐1 were analyzed on a quadrupole‐Orbitrap. We monitored the dissociation of ADPr (+ 541.061 Da) to phosphoribosyl‐H2O (+ 193.997 Da) peptides while varying the source and high‐field asymmetric waveform ion mobility mass spectrometry (FAIMS) compensation voltages. Xcorr and ptmRS were used to evaluate peptide sequencing and acceptor site confidence, respectively. Phosphoribosyl‐H2O acceptor sites were compared with those determined by electron‐transfer higher‐energy collision dissociation (EThcD), performed on a quadrupole‐ion trap‐Orbitrap. Results In‐source CID of ADPr peptides to their phosphoribosyl‐H2O derivatives increased with increasing source voltage (up to 50 V), as judged by monitoring the corresponding modification loss ([adenosine monophosphate/AMP]⁺) and the number of identified phosphoribosyl‐H2O peptide identifications. The average Xcorr increased from 1.36 (ADPr) to 2.26 (phosphoribosyl‐H2O), similar to that achieved with EThcD for ADPr peptides (2.29). The number of high‐confidence acceptor sites (> 95%) also increased, from 31% (ADPr) to 70% (phosphoribosyl‐H2O), which was comparable to EThcD (70%). Conclusions In‐source CID converts ADP‐ribosyl to phosphoribosyl‐H2O peptides that are more amenable to HCD‐dependent peptide sequencing, providing an alternative method for acceptor site determination when ETD‐based methods are not available.

Macrophage activation syndrome (MAS) is a state of immune hyperactivation that can result in life‐threatening multisystem end‐organ dysfunction. Often termed a “cytokine storm,” MAS occurs among the rheumatic diseases most typically in Still's disease but also in systemic lupus erythematosus and Kawasaki disease. MAS can also accompany infection, malignancy, and inborn errors of immunity. This review provides a practical, evidence‐based guide to the understanding, recognition, and management of MAS in children and adults, with a primary focus on MAS complicating Still's disease.

Subthalamic (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients not only improves kinematic parameters of movement but also modulates cognitive control in the motor and non‐motor domain, especially in situations of high conflict. The objective of this study was to investigate the relationship between DBS‐induced changes in functional connectivity at rest and modulation of response‐ and movement inhibition by STN‐DBS in a visuomotor task involving high conflict. During DBS ON and OFF conditions, we conducted a visuomotor task in 14 PD patients who previously underwent resting‐state functional MRI (rs‐fMRI) acquisitions DBS ON and OFF as part of a different study. In the task, participants had to move a cursor with a pen on a digital tablet either toward (automatic condition) or in the opposite direction (controlled condition) of a target. STN‐DBS induced modulation of resting‐state functional connectivity (RSFC) as a function of changes in behavior ON versus OFF DBS was estimated using link‐wise network‐based statistics. Behavioral results showed diminished reaction time adaptation and higher pen‐to‐target movement velocity under DBS. Reaction time reduction was associated with attenuated functional connectivity between cortical motor areas, basal ganglia, and thalamus. On the other hand, increased movement velocity ON DBS was associated with stronger pallido‐thalamic connectivity. These findings suggest that decoupling of a motor cortico‐basal ganglia network underlies impaired inhibitory control in PD patients undergoing subthalamic DBS and highlight the concept of functional network modulation through DBS.

Background Newborns with critical congenital heart disease (CCHD) require specialized delivery room management, but varying experience and knowledge can reduce confidence and impact care. Methods A pre-delivery, structured huddle checklist was introduced, addressing team roles, expected physiology, and management plans. PDSA cycles incorporated guidelines and simulation-based education to improve confidence in specialized resuscitation strategies. Surveys were conducted at baseline and 6 months. Results Baseline, all-respondent confidence in managing “all types of CCHD” was somewhat confident (median 3/5; IQR 2–4) increasing to moderately confident (4/5; IQR 2–4) at 6 months (p = 0.59). Respondents with 0–3 years’ experience showed increased confidence over 6 months in identifying unstable infants (from baseline 24% to 67% moderately/very confident, p = 0.005), prostaglandin E1 needs (from 24% to 62%, p = 0.013) and sedation requirements (from 5% to 33%, p = 0.045). Conclusion Structured huddles improved confidence among less experienced team members, emphasizing the importance of shared mental models before CCHD deliveries.

Background The 2022 WHO guidelines on multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) recommend six months of bedaquiline (Bdq) in the all-oral 9-month shorter regimen and six months or longer for Bdq and delamanid (Dlm) in the 18-20-month longer regimen. However, lack of evidence on extended treatment using Bdq or Dlm has limited their use to six months. We examine the frequency and incidence of QT prolongation based on duration of Bdq and/or Dlm use in longer regimens. Methods We analyzed a prospective cohort of MDR/RR-TB patients from 16 countries who initiated treatment with Bdq and/or Dlm containing regimens from 1 April 2015-30 September 2018. Data were systematically collected using a shared protocol. The outcome of interest was the first clinically relevant prolonged QT interval (grade 3 or above) or a Serious Adverse Event (SAE) involving prolonged QT of any grade. Results Among 2,553 patients, 59% received >6 months of Bdq and/or Dlm. Of these, 579 (20.9%) patients experienced a prolonged QT event, the majority (95.5%) being grade 1 or 2. Sixty-four(2.5%) patients experienced the outcome of interest with only 12 (0.5%) having ≥ 1 QT prolonging drugs permanently suspended. The incidence rate of the first prolonged QT event was highest in the first six months of treatment and lower in subsequent six-month periods. Conclusion We demonstrate that Bdq and/or Dlm use beyond six months is safe in longer MDR/RR-TB regimens with most clinically relevant QT prolongation events occurring in the first six months. ECG monitoring for early identification of QT prolongating events is possible in programmatic conditions.

Cancer immunotherapy has revolutionized cancer treatment by leveraging the immune system to target and eliminate tumor cells. Implantable biomaterials, such as hydrogels, sponges, scaffolds, implantable microdevice platforms, and macrobeads, offer localized and sustained release of immunomodulatory agents, improving the delivery of treatments such as immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapies like CAR‐T cells. This review examines the emerging role of these biomaterials in modulating the tumor microenvironment, enhancing immune cell recruitment, and reducing systemic side effects, positioning them as significant tools for treating solid tumors. Recent advances in material engineering are also discussed, including the integration of bioactive molecules and real‐time therapeutic adjustments based on patient‐specific immune responses, which offer new potential in personalized cancer treatments. However, challenges such as biocompatibility, high production costs, variability in patient response, and the necessity of surgical manipulations remain key obstacles. Nonetheless, ongoing research and technological advancements are steadily addressing these issues, paving the way for more effective and accessible cancer immunotherapies. Overall, this review highlights the promise of implantable biomaterials overcoming the current limitations of cancer immunotherapy and expanding the scope of effective, targeted cancer treatments.

Introduction There is a lack of evidence regarding the impact of donor blood transfusion on heart transplant (HT) outcomes. We sought to elucidate the influence of donor transfusion on HT outcomes using the national database. Methods From January 2004 to March 2023, donor transfusion information was available for 40 538 recipients for HT in the United Network for Organ Sharing (UNOS) database. We used the UNOS 4‐level designation of transfusion (no blood [ N = 18 575], 1–5 units [ N = 14 098], 6–10 units [ N = 4766], and massive transfusion of > 10 units [ N = 3099]). Results Among this cohort, 53.2% of donors ( N = 20 220) received a blood transfusion during the same admission. Donors who required blood transfusion commonly had head trauma as a cause of death (no‐blood, 22% vs. 1–5 units, 61%, 6–10 units, 88%, massive, 89%, p < 0.001). An increased amount of donor blood transfusion did not affect rates of acute rejection (no‐blood, 18% vs. 1–5 units, 19%, 6–10 units, 17%, massive, 19%, p = 0.13). The number of units transfused also did not affect 1‐year survival rates. The Cox hazard model showed no effect of massive transfusion on mortality following transplant (no‐blood, reference vs. 1–5 units; HR, 1.02 [ p = 0.35], 6–10 units; HR, 1.10 [ p = 0.01], massive transfusion; HR 1.04 [ p = 0.3]). Conclusions Massive transfusion in donors was not associated with increased recipient mortality. Additionally, the amount of donor blood transfusion did not affect rejection rates following HT. The present study suggests that a history of donor blood transfusion, as well as the amount of transfusion, should not preclude donor heart utilization.

Clinical trial design for classical hematologic diseases is difficult because samples sizes are often small and not representative of the disease population. ASH initiated a Roadmap project to identify barriers and make progress to integrate diversity, equity, and inclusion into trial design and conduct. Focus groups of international experts from across the clinical trial ecosystem were conducted. Eight issues identified include: 1) Harmonization of demographic terminology; 2) Engagement of lived experience experts across the entire study timeline; 3) Awareness of how implicit biases impede patient enrollment; 4) The need for institutional review boards to uphold the justice principle of clinical trial enrollment; 5) Broadening of eligibility criteria; 6) Decentralized trial design; 7) Improving access to clinical trial information; and 8) Increased community physician involvement. By addressing these issues, the hematology community can promote accessible and inclusive trials that will further inform research, clinical decision making, and care for patients.

We identified 347 pregnancies in patients with beta thalassemia minor. Hemoglobin was below 9 g/dL in 31% during third trimester and 7.6% at delivery. Postpartum hemorrhage occurred in 8.9%. Forty-six percent of intravenous iron administration was to iron-replete patients.

Aims Unusual morphologic patterns of breast carcinomas can raise diagnostic consideration for metastasis or special breast cancer subtypes with management implications. We describe rare invasive breast cancers that mimic serous carcinoma of the gynaecologic tract (serous‐like breast carcinomas, SLBC) and characterize their clinicopathologic, immunophenotypic, and genetic features. Methods and Results All patients were female ( n = 15, median age 49 years) without a history of gynaecologic malignancy. SLBC were characterized histologically by angulated, branched, sometimes anastomosing glands with micropapillary and/or pseudopapillary luminal projections in desmoplastic stroma. Most SLBC were triple‐negative (TN, n = 10) or HER2‐positive ( n = 2) and grade 2 or 3, while some were oestrogen receptor (ER) low‐positive/HER2‐negative and low‐grade ( n = 3). CK5/6 was positive irrespective of grade or receptor status (10/10). All SLBC expressed GATA3 (14/15), TRPS1 (7/7), and/or mammaglobin (4/13). SOX10 was positive in most TN (9/10) and all ER low‐positive (3/3) cases, but negative in HER2‐positive tumours. WT1 was universally negative, and PAX8 was focal in one mammaglobin‐positive tumour. All ER‐negative SLBC were p53‐aberrant and 9/11 were p16‐aberrant, whereas ER‐positive tumours were wildtype for both markers (3/3). TP53 was the only frequently mutated gene, altered in all ER‐negative (10/10) but no ER‐positive (0/4) tumours. Clinical behaviour was variable. Only 1/6 patients achieved pathologic complete response to neoadjuvant chemotherapy. Conclusion SLBC is a rare morphologic pattern of invasive breast carcinoma that mimics metastatic serous gynaecologic carcinoma, a potential diagnostic pitfall. SLBC are heterogeneous with respect to grade, receptor profile, and oncogenic driver alterations, without specific genetic underpinnings identified. Additional studies are warranted to further evaluate the clinical behaviour of these tumours.

Central Message Underrepresentation of women in surgical specialties persists, especially in academic leadership roles. Efforts to better understand disparities and support women cardiothoracic surgeons are ongoing.

This study aimed to describe what is known in the scientific literature about patient-reported experience measures (PREMs) in pediatric healthcare and identify areas for further exploration. PubMed, Web of Science, CINAHL, Google Scholar, COCHRANE, and SveMed+ combined with free text search in FireFox and Safari web browsers using Medical Subject Headings terms were used. Outcomes of interest were patient experience and measures of these constructs. Of the 316 studies identified, 68 met the inclusion criteria. Forty-eight studies (72%) were published between 2015 and 2020 and more than half (53%) were published in Europe. Most studies of PREMs in pediatric healthcare included adult proxies as participants. Seventy-eight percent of studies consisted of > 100 participants. Thirty-six studies (53%) were quantitative studies, 26 (38%) were evaluative studies of patient experience measures, and 6 (9%) were qualitative in design. Three hundred eleven domains were identified and further categorized into 14 domain areas. This research is important because it aims to amplify the voices of children in healthcare and establish a foundation for developing validated pediatric-PREMs that is grounded in children's firsthand experiences of care, rather than relying primarily on proxy accounts.

Endovascular interventions are procedures designed to diagnose and treat vascular diseases, using catheters to navigate inside arteries and veins. Thanks to their minimal invasiveness, they offer many benefits, such as reduced pain and hospital stays, but also present many challenges for clinicians, as they require specialized training and heavy use of X‐rays. This is particularly relevant when accessing (i.e. cannulating) small arteries with steep angles, such as most aortic branches. To address this difficulty, a novel solution that enhances fluoroscopic 2D images in real‐time by displaying virtual configurations of the catheter and guidewire is proposed. In contrast to existing works, proposing either simulators or simple augmented reality frameworks, this approach involves a predictive simulation showing the resulting shape of the catheter after guidewire withdrawal without requiring the clinician to perform this task. This system demonstrated accurate prediction with a mean 3D error of 2.4 ±$\pm$ 1.3 mm and a mean error of 1.1 ±$\pm$ 0.7 mm on the fluoroscopic image plane between the real catheter shape after guidewire withdrawal and the predicted shape. A user study reported an average intervention time reduction of 56%$\%$ when adopting this system, resulting in a lower X‐ray exposure.

Cervical radicular pain following anterior cervical discectomy and fusion (ACDF) is a challenging condition, particularly in the presence of hardware complications. This case report discusses the successful use of a cervical interlaminar steroid injection to alleviate radicular pain in a patient who presented with a fractured screw following C6/7 ACDF. The patient’s symptoms, treatment plan, and outcome are reviewed, highlighting the success of an interlaminar steroid injection in managing radicular pain until the patient could receive corrective surgery.

Subgroup analyses are essential to generate new hypotheses or to estimate treatment effects in clinically meaningful subgroups of patients. They play an important role in taking the next step towards personalized surgical treatment for brain tumor patients. However, subgroup analyses must be used with consideration and care because they have significant potential risks. Although some recommendations are available on the pearls and pitfalls of these analyses, a comprehensive guide is lacking, especially one focused on surgical neuro-oncology patients. This paper, therefore, reviews and summarizes for the first time comprehensively the practical and statistical considerations that are critical to this field. First, we evaluate the considerations when choosing a study design for surgical neuro-oncology studies and examine those unique to this field. Second, we give an overview of the relevant aspects to interpret subgroup analyses adequately. Third, we discuss the practical and statistical elements necessary to appropriately design and use subgroup analyses. The paper aims to provide an in-depth and complete guide to better understand risk modeling and assist the reader with practical examples of designing, using, and interpreting subgroup analyses.

Squamous cell carcinoma of the vulva (vSCC) is currently categorized either as human papillomavirus (HPV) associated or independent. Immunohistochemical stains, p16 INK4a (p16) and p53 are helpful biomarkers to support the designation of vSCC into 1 of the 3 tumor pathways: (1) HPV-associated, (2) HPV-independent, TP53 mutant, or (3) HPV-independent, TP53 wild type. Recently, a framework of p53 expression patterns in vSCC was proposed. In this international and multi-institutional study, we evaluated the interrater agreement for p53 and p16 and tumor pathway classification in a cohort of 50 invasive vSCC across a variety of practice settings (private practice, academic medicine) and levels of expertise (trainees, gynecologic pathologists, dermatopathologists, private practice pathologists). Our study shows that the overall interrater agreement for the interpretation of p16 in vSCC is strong to near perfect, while the agreement for p53 and tumor pathway assignment is overall moderate. Interrater agreement for p53 and tumor pathway is higher (strong) in the academic practice setting. Pathologists without gynecologic subspecialty expertise benefited the most from a brief educational module, which fostered a better understanding and improved comfort level with the p16/p53 stain interpretation and tumor pathway designation in the diagnosis of vSCC. Some interpretative challenges remain, particularly in regard to select p53 patterns and high-risk HPV-in situ hybridization utilization, warranting additional research.

Background and purpose. This study presents machine learning (ML) models that predict if deep inspiration breath hold (DIBH) is needed based on lung dose in right-sided breast cancer patients during the initial computed tomography (CT) appointment. Materials and methods. Anatomic distances were extracted from a single-institution dataset of free breathing (FB) CT scans from locoregional right-sided breast cancer patients. Models were developed using combinations of anatomic distances and ML classification algorithms (gradient boosting, k-nearest neighbors, logistic regression, random forest, and support vector machine) and optimized over 100 iterations using stratified 5-fold cross-validation. Models were grouped by the number of anatomic distances used during development; those with the highest validation accuracy were selected as final models. Final models were compared based on their predictive ability, measurement collection efficiency, and robustness to simulated user error during measurement collection. Results. This retrospective study included 238 patients treated between 2016 and 2021. Model development ended once eight anatomic distances were included, and the validation accuracy plateaued. The best performing model used logistic regression with four anatomic distances achieving 80.5% average testing accuracy, with minimal false negatives and positives (< 27%). The anatomic distances required for prediction were collected within 3 minutes and were robust to simulated user error during measurement collection, changing accuracy by < 5%. Conclusion. Our logistic regression model using four anatomic distances provided the best balance between efficiency, robustness, and ability to predict if DIBH was needed for locoregional right-sided breast cancer patients.