Citations

Abstract Background For many evidence criteria within v3.0 of the ACMG/AMP guidelines, methodologies have been developed to empower their use outside the stipulated evidence strengths. However, no such methodology has been established for case-control data (PS4). With the release of large-scale unselected case-control datasets and expansion of nationally-collected laboratory datasets enriched for pathogenic variant carriers, there is potential to combine datasets across ascertainment contexts in a more quantitative manner using novel likelihood ratio tools. Methods Using our published PS4-LR-Calculator, we calculated a combined log likelihood ratio (PS4-LLR) across five datasets (three unselected, and two enriched), and estimated enrichment of pathogenic variants in clinically-ascertained laboratory data using truncating variant prevalence. Results Data were combined for 10,817 missense variants from 325,345 female breast cancer patients and 671,006 controls of Western European ancestry for five breast cancer susceptibility genes ( BRCA1, BRCA2, PALB2, ATM, CHEK2 ). A combined LLR was produced for 4,690 missense variants; 927 variants received evidence towards pathogenicity (LLR≥ 1), and 3,242 received evidence towards benignity (LLR≤ -1). Conclusion This flexible, variant-level methodology combines nationally-collected ‘enriched’ datasets with unselected case-control cohorts, expanding the available information for case-control analysis, boosting power, enabling exploration of atypical penetrance and empowering variant classification.

Abstract Background The most compelling advantage that photon counting detectors (PCDs) currently have over energy integrating detectors (EIDs) for CT applications may be their improved spatial resolution. However, PCDs are difficult to manufacture. Next‐generation EIDs using conventional scintillator sensors could be easier to mass produce, but their spatial resolution is thought to be limited by fill factor considerations. Specifically, each EID pixel comprises a block of scintillator surrounded by inactive, optically reflective septa. The minimum width of optically reflective septa is ∼0.1 mm, and unless this is shrunk, decreases in pixel pitch inevitably cause an increasing fraction of dead space. Purpose To propose a modified system geometry in which the detector pixels are tilted by a few degrees, such that rays that are incident on reflective septa would later encounter scintillator. Because reflective septa are nearly transparent to x‐rays compared to scintillator, this geometry restores much of the lost fill factor. Methods Tilting can be achieved in several different ways. We discuss three implementation options: individual detector modules may be tilted, with gaps between modules that are seamless from the perspective of the x‐ray source; the whole detector can be arranged to point towards a “false” focal spot that is offset slightly from the true focal spot; the scintillator wafer can structured differently, e.g. by sawing it at an angle. The pros and cons of each option are discussed. Tilting introduces blurring, but a smaller pixel size improves resolution, and the combination of both improves both resolution and fill factor. We used Monte Carlo simulations to compare a conventional detector with 1.0 mm, 0.75, or 0.5 mm pixel pitch to a tilted detector with 0.5 mm pixel pitch. We assumed negligible optical crosstalk and electronic noise, that the scintillator was 1.5 mm thick with attenuation similar to gadolinium oxysulfide, that the reflective septa was 0.1 mm wide at standard resolution or 0.08 mm at higher resolutions and composed of a low‐attenuating polymer similar to acrylic infused with 20% titanium content. We also compared this to a simple model of a CdTe detector with 1.6 mm thickness, 0.3 mm pixel pitch, and Gaussian charge sharing. Results Tilt increases the aperture of the pixel in an energy‐dependent fashion. With a 1D ASG (85% fill factor) and at 120 kVp, the detection efficiencies (DQE(0)) of a conventional detector at 1.0 mm, conventional detector at 0.5 mm pixel pitch, CdTe detector, and tilted detector at 0.5 mm pixel pitch are 65%, 55%, 66%, and 64%, respectively. With a sparse 2D ASG (1.5 × 3.0 mm openings, 86% fill factor), the DQE(0) of a tilted detector with 0.75 mm is 69%. The DQE(0) of all detectors decreases at higher energy because of punch‐through. Conclusions By tilting detector modules a few degrees, energy‐integrating detectors can provide increases in spatial resolution without the expected losses in fill factor. This architecture could bring the resolution improvements associated with photon counting CT into the domain of energy‐integrating detectors equipped with conventional scintillator sensors.

PURPOSE We tested the hypothesis that adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy improves progression-free survival (PFS) among patients with oligometastatic disease. METHODS EXTEND was a multicenter randomized phase II trial. Patients with 1-5 metastases were randomly assigned to MDT + SOC versus SOC in one of the six baskets (breast, pancreas, kidney, two prostate baskets, and an other basket) with basket-specific stratification and powering. PFS, the primary end point, was prespecified in the per-protocol set within each basket, across all baskets, and across all baskets excluding the prostate baskets. Exploratory end points included circulating tumor DNA (ctDNA) and immune profiling. RESULTS From 2018 through 2023, 521 patients were screened, 350 were randomly assigned, and 334 were analyzed per protocol (MDT + SOC, n = 166; SOC, n = 168). Radiotherapy was used as MDT for 98% of metastases (370/379). Overall, after a median follow-up of 53 months, PFS was improved with MDT + SOC (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.72], P < .001). Similarly, PFS was improved when excluding the prostate baskets (HR, 0.60 [95% CI, 0.40 to 0.89]). Within each basket, PFS superiority was identified for the pancreas, prostate, and other baskets, whereas the breast and kidney baskets were inconclusive. At enrollment, detectable ctDNA correlated with shorter PFS and survival; by contrast, ctDNA clearance 3 months postenrollment correlated with improved survival. MDT + SOC-induced systemic immune activation was most pronounced among baskets demonstrating PFS superiority. CONCLUSION The phase II EXTEND trial supports the addition of MDT to SOC for oligometastatic disease. Histology-specific efficacy signals were identified for phase III testing. Translational insights suggest the potential for optimizing the definition of oligometastasis using ctDNA and point to systemic immune responses as a possible mechanism of benefit from MDT.

ABSTRACT Objective This study examines the knowledge, beliefs, and perceptions of asthma among caregivers in Bogotá, Colombia, a middle‐income country (MIC). It provides insights into how these factors influence self‐management and adherence. Methods Trained facilitators conducted focus groups composed of caregivers of asthmatic children. Interview data were analyzed and coded using a process of open coding transcription, followed by inductive thematic‐based coding. The basic codes were then elaborated into a framework of thematic categories within NVivo. Results Sixteen caregivers were divided into two focus groups. Knowledge, beliefs, and perceptions about asthma and inhalation therapy, interactions between caregivers and other individuals, the use of traditional and natural medicine, and the availability of essential medications for asthma therapy were highlighted by the participant caregivers. Although some of the issues identified in these topics are similar to those described in high‐income countries, there are some differences, particularly regarding the fears of patients developing addiction to medications due to the use of inhalation therapy in childhood, the lifelong requirement of inhalation therapy, and the use of traditional versus natural medicine. Conclusions The present study's findings provide insights into how caregivers understand asthma and its treatment in their children. These insights can serve as a basis for more targeted and effective educational interventions in Colombia and other countries with similar socio‐economic and cultural conditions.

Abstract Introduction Sexual problems are common throughout the lifespan. Therefore, it is important for medical students and other health professionals to receive instruction in sexual medicine that is sufficient to prepare them to address these issues as a routine part of practice. Objectives To consolidate and update recommendations published from prior International Consultations on Sexual Medicine and other consensus-based recommendations from across the world for standards of sexual health education (SHE) among medical students. To evaluate the status of recommendations for various health professionals and of existing training and educational platforms. Methods A conceptual review of previous reports on curriculum standards of SHE in medical schools and an updated literature review from 2016 to current was conducted. Results We provide a summary and comprehensive recommendations based on expert opinion, accumulated experience, and literature review for a sexual health curriculum for medical students, including how it should be taught, recognizing that curricula are diverse worldwide. Scant research exists regarding the impact of sexual medicine training on sustained clinical skills and patient outcomes. Existing sexual medicine education platforms can be applied, adapted, and optimized across training levels, disciplines, and geographic locations. We discuss opportunities to improve evaluation of knowledge and competency, as well as the importance of studying methodologies to improve curriculum and methods of evaluation, particularly for disciplines in which these curricula have not previously been evaluated. Conclusions Sexual medicine societies are encouraged to implement previous recommendations and make medical student SHE a priority. Extending these recommendations to post-graduate and practicing clinician and other health professionals’ education would help close education and clinical practice gaps. Future training interventions should incorporate assessment of skill acquisition and meaningful patient outcomes, as well as integrate educational platforms including web-based formats, interactive technology, and experiential learning strategies. Recommendations of Expert Consensus Committee Sexual health educational curricula should be expanded to include sexual well-being and pleasure in addition to pregnancy and sexually transmitted infection (STI) prevention. (Strong) ISSM and affiliated sexual medicine societies (ASMS) should follow through on previous recommendations (ICSM 2009, 2016) and prioritize sexual health education in their missions. (Strong) Sexual medicine societies should join with other organizations to promote standards through position statements and other joint efforts. (Strong) ISSM/ASMS should play a key role in setting curriculum standards, promoting sexual health education in medical schools and other health professions, providing teaching methods and materials, and training of educators. (Strong) ISSM/ASMS are encouraged to establish standing committees promoting sexual medicine education in medical schools, other health professions, and graduate/postgraduate training. (Weak) ISSM/ASMS should utilize international, regional, and virtual meetings as vehicles for disseminating updated knowledge and training educators. (Strong) ISSM/ASMS should advocate to regulatory organizations that set standards for the requirement of sexual health training and assessment of competency in all professions. (Strong) The committee encourages exploration of the use of digital interactive platforms and modern technologies (avatars, AI -artificial intelligence, NLP -natural language processing) and inclusion of quality assurance of virtual domains. (Weak) Beyond the evaluation of student and postgraduate trainee performance and curricula effectiveness, the committee urges research on the impact of educational interventions on sustained clinical practices and patient outcomes in sexual health. (Strong)

Purpose To investigate the clinical features, treatments, and outcomes of patients with secondary orbital lymphoma. Major Findings In this cohort of 31 patients, 15 (48.4%) were female and 27 (87.1%) were white. Follicular lymphoma was the most common subtype (n = 13, 41.9%) and was more associated with unilateral disease compared to other subtypes (p = 0.01). Common presenting symptoms included a palpable mass (n = 17, 54.8%), eyelid swelling (n = 16, 51.6%), and ptosis (n = 12, 38.7%). Patients were most often diagnosed with Ann Arbor Stage IV lymphoma (n = 17, 54.8%) via incisional biopsy (n = 13, 41.9%). Radiation therapy (n = 9, 29.0%) was the most common initial treatment, and most patients received radiation (n = 19, 61.3%) and/or chemotherapy (n = 21, 67.7%). A majority of patients had final best corrected visual acuity (BCVA) within 1 line of initial BCVA (n = 19, 82.6%) and had no local recurrences (n = 21, 67.7%). However, complete remission was rare (n = 3, 9.7%), and systemic recurrence occurred in over half of patients (n = 18, 58.1%). Conclusions Follicular lymphoma was the predominant subtype of secondary orbital lymphoma in this cohort. Most patients with secondary orbital lymphoma presented with advanced disease where few achieved complete remission and more than half of the patients developed systemic recurrence despite majority retaining visual acuity.

Objectives To compare patients’ perception of their degree of subglottic stenosis to their endoscopic exam findings, Clinical Dyspnea Questionnaire, and peak flow results. Study Design Prospective Multi-Institutional. Setting Tertiary Care Clinic. Methods A study of 50 patients comparing patients’ perception of their degree of subglottic stenosis to their endoscopic exam findings. All patients filled out a Clinical Dyspnea Questionnaire and a 10-point scale reflecting their perceived degree of stenosis in 10% intervals. Surgeons filled out the same scale based on measurements from the patients’ exam. Accuracy was defined as +/-1 on a 10-point scale. Pulmonary function testing, number of dilation procedures undergone, cause of stenosis, and demographic information were collected. Results Data complete for 49/50 patients. 48 (98%) were female, 47 (97.9%) Caucasian, 44 (89.8%) had idiopathic subglottic stenosis, and 28 (58.3%) had Grade I subglottic stenosis on the Cotton-Meyer scale. Spearman correlation coefficient was 0.67 indicating moderate correlation overall but 0.88, or high correlation, for those with normal Body Mass Index. Increased Dyspnea Index scores and higher Body Mass Index were correlated with decreased accuracy. Number of previous procedures was not correlated with accuracy. Higher Body Mass Index was correlated with increased dyspnea and lower peak flow volume. Conclusion Patients with normal Body Mass Index have strong predictive accuracy regarding their degree of subglottic stenosis. Better dyspnea scores were correlated with improved accuracy. There is no standard consensus on subglottic stenosis patient follow up. Prior studies have looked at using peak flow meters and validated questionnaires to monitor symptoms.

OBJECTIVE The aim of this study was to evaluate freedom from tumor progression and clinical outcomes in older adults with small- to medium-sized vestibular schwannoma (VS) managed by observation versus stereotactic radiosurgery (SRS) to better inform optimal management in this patient population. METHODS In this international multicenter study, patients aged ≥ 60 years with Koos grade I or II VS managed by observation or SRS were retrospectively reviewed. Propensity score matching was conducted using patient characteristics, tumor size, and hearing assessments. Outcome measures of freedom from tumor progression, serviceable hearing preservation (SHP), and neurological function (tinnitus, vestibulopathy, House-Brackmann grade, and trigeminal nerve function) were assessed for both groups. RESULTS The observation and SRS groups each comprised 51 matched patients (median age 68 years for both). Ipsilateral serviceable hearing was observed at presentation for 35 patients in each group. The median follow-up duration was 39 months in the observation group versus 27 months in the SRS group (p = 0.5). Tumor progression was significantly lower with SRS than with observation (2% vs 52.9%, p < 0.001). The rate of 5-year freedom from tumor progression was 100% in the SRS group versus 43% (95% CI 29%–64%) in the observation group. The rate of 10-year freedom from tumor progression was 90% (95% CI 73%–100%) in the SRS group versus 20% (95% CI 8.5%–49%) in the observation group. At the last follow-up, hearing loss occurred in 42.9% of the observation group and 51.4% of those who underwent SRS (p = 0.5). The 3-year SHP rate was 68% (95% CI 53%–88%) versus 65% (95% CI 49%–85%) (p = 0.8), and the 5-year SHP rate was 53% in both groups (95% CI 36%–78% in the observation group and 95% CI 35%–79% in the SRS group, p = 0.8). The composite endpoint of tumor progression and/or worsened neurological outcome, including hearing loss, tinnitus, vestibulopathy, facial nerve dysfunction (House-Brackmann grade), or trigeminal dysfunction, demonstrated a significantly lower rate in the SRS group (17.6%) compared with the observation group (66.7%) (p < 0.001). CONCLUSIONS SRS in older patients for management of Koos grade I or II VS resulted in significantly superior rates of freedom from tumor progression, comparable hearing preservation rates, and significantly higher rates of favorable overall radiographic and neurological outcomes than observation alone. Compared with observation, SRS might be the preferred management option in this patient population.