Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) infection causes considerable illness in older adults. The efficacy and safety of an investigational bivalent RSV prefusion F protein-based (RSVpreF) vaccine in this population are unknown. METHODS: In this ongoing, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults (≥60 years of age) to receive a single intramuscular injection of RSVpreF vaccine at a dose of 120 µg (RSV subgroups A and B, 60 µg each) or placebo. The two primary end points were vaccine efficacy against seasonal RSV-associated lower respiratory tract illness with at least two or at least three signs or symptoms. The secondary end point was vaccine efficacy against RSV-associated acute respiratory illness. RESULTS: At the interim analysis (data-cutoff date, July 14, 2022), 34,284 participants had received RSVpreF vaccine (17,215 participants) or placebo (17,069 participants). RSV-associated lower respiratory tract illness with at least two signs or symptoms occurred in 11 participants in the vaccine group (1.19 cases per 1000 person-years of observation) and 33 participants in the placebo group (3.58 cases per 1000 person-years of observation) (vaccine efficacy, 66.7%; 96.66% confidence interval [CI], 28.8 to 85.8); 2 cases (0.22 cases per 1000 person-years of observation) and 14 cases (1.52 cases per 1000 person-years of observation), respectively, occurred with at least three signs or symptoms (vaccine efficacy, 85.7%; 96.66% CI, 32.0 to 98.7). RSV-associated acute respiratory illness occurred in 22 participants in the vaccine group (2.38 cases per 1000 person-years of observation) and 58 participants in the placebo group (6.30 cases per 1000 person-years of observation) (vaccine efficacy, 62.1%; 95% CI, 37.1 to 77.9). The incidence of local reactions was higher with vaccine (12%) than with placebo (7%); the incidences of systemic events were similar (27% and 26%, respectively). Similar rates of adverse events through 1 month after injection were reported (vaccine, 9.0%; placebo, 8.5%), with 1.4% and 1.0%, respectively, considered by the investigators to be injection-related. Severe or life-threatening adverse events were reported in 0.5% of vaccine recipients and 0.4% of placebo recipients. Serious adverse events were reported in 2.3% of participants in each group through the data-cutoff date. CONCLUSIONS: RSVpreF vaccine prevented RSV-associated lower respiratory tract illness and RSV-associated acute respiratory illness in adults (≥60 years of age), without evident safety concerns. (Funded by Pfizer; RENOIR ClinicalTrials.gov number, NCT05035212; EudraCT number, 2021-003693-31.).

Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants.

BACKGROUND: Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. METHODS: In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points. RESULTS: At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively). CONCLUSIONS: RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.).

Rural Emergency Medical Services Clinicians' Perceptions and Preferences in Receiving Clinical Feedback From Hospitals: A Qualitative Needs Assessment.

OBJECTIVE: Emergency medical services (EMS) clinicians experience dissatisfaction with the quality and quantity of clinical feedback from hospitals. Satisfaction is further diminished by the lack of a standardized systems approach. The purpose of this study was to identify rural clinicians' perceptions and preferences regarding clinical feedback received from hospitals, the delivery mechanisms, and its impact on their relationships with health care organizations. METHODS: This was a qualitative study focused on EMS clinicians involved in rural prehospital care at a single Midwestern academic medical center. Using a phenomenological framework, semi-structured interviews were conducted with medical directors, service directors, fire captains, air medical personnel, emergency medical responders, emergency medical technicians, advanced emergency medical technicians, and paramedics, all of whom were selected through purposive sampling. Interviews were recorded, transcribed, and independently coded by two trained reviewers. RESULTS: Twenty participants (11 frontline clinicians and 9 administrative staff members) with a wide range of clinical experience from 14 air and ground EMS agencies were interviewed. Emerging themes included: (1) the value or usefulness of feedback; (2) desired feedback system characteristics; (3) barriers to receiving feedback; (4) utilization and application of feedback; and (5) the feedback's impact on the relationship with health care organizations. Participants felt that clinical feedback from hospitals was especially important as a method of improving quality of care, though was rarely provided. Professional development was seen as a major benefit of receiving clinical feedback from hospitals. CONCLUSION: Our results suggest that consistent clinical feedback provided by hospitals was valued. Establishing a culture of providing organized feedback to practicing rural EMS clinicians is important for professional development and can strengthen the relationships between EMS clinicians and hospitals. These study findings can assist in the development and implementation of a standardized feedback instrument to benefit rural EMS clinicians, patients, and the health care system as a whole.

Spontaneous epiglottic hematoma secondary to direct oral anticoagulant.

Spontaneous hemorrhage is a known risk for patients on anticoagulation therapy. Most previous spontaneous airway hemorrhage cases reported involve warfarin, and of the few that involved a direct oral anticoagulant, none involved the epiglottis. The following case describes a spontaneous epiglottic hematoma in a patient one week after starting a direct oral anticoagulant. An 85-year-old man presented to the emergency department with acute onset of neck swelling, odynophagia and sublingual ecchymosis. Evaluation in the emergency department included advanced imaging of the neck and consultation with otolaryngology. Flexible fiberoptic laryngoscopy showed a markedly enlarged and ecchymotic epiglottis. The patient received medical management including rivaroxaban reversal, steroids, and broad-spectrum antibiotics, but no airway management was deemed necessary. After close monitoring, the patient was discharged on hospital day two. Further research and risk profiling could benefit patients and emergency clinicians when considering spontaneous hemorrhage in the airway in patients taking a direct oral anticoagulant.

Issues Arising in Psychological Consultations to Help Parents Talk to Minor and Young Adult Children about their Cancer Genetic Test Result: a Guide to Providers.

The defining difference between genetic and traditional medicine is that genetic findings have implications not just for the patient, but also for their relatives. Discussion of a test result between parent and child is both a transformative and a translational moment in the life of a family. Parents report wanting help in talking to their children. The challenge for genetic counselors and other providers is to be able to recognize which issues are at the core of parental distress and be able to offer recommendations to empower and support parents. The complexity of potential genetic findings, including variants of uncertain significance (VUS) and incidental findings have vastly increased, requiring considerable explanation and leaving less time for discussion of emotional issues. While the nature of the testing (single gene to multigene panel and genomic testing) is dramatically changing, the nature of parent concerns remains remarkably constant. Families differ in many respects, so no "recipe" suffices to answer parents' questions about how this important task should be approached in each family. Successful consultation to parents requires true counseling, matching parents' fears and questions with information, exploration and advice specific to their concerns, their circumstances and strengths.

Improving Outcomes in Patients Sent to the Emergency Department from Outpatient Providers: A Receiver-Driven Handoff Process Improvement.

BACKGROUND: Outpatient providers refer to emergency departments (EDs) due to findings requiring assessment beyond existing capabilities. However, poor communication surrounding these transitions may hinder safety and timeliness of emergency care. Receiver-driven handoff (RDH) is a process that helps ensure that all pertinent information is shared. This quality improvement project aimed to (1) improve knowledge of RDH, (2) increase satisfaction and perceptions surrounding RDH, (3) modify behaviors in relation to RDH, and (4) decrease referred patients leaving without being seen (LWBS). METHODS: The Iowa Model and Implementation Framework guided this evidence-based quality improvement project. A multidisciplinary team developed and implemented a standardized RDH process consisting of screening to determine whether a patient was referred to the ED, review of electronic health record (EHR), and use of EHR documentation. Process measures were collected via questionnaire pre- and postimplementation and were analyzed quantitatively. Outcome measures were trended by a statistical process control p-chart, which was developed to demonstrate changes in the percentage of patients who were referred to the ED from the outpatient setting and LWBS. RESULTS: The average response for the question "How satisfied are you with the handoff of patient information from referring clinic providers to the ED?" increased from 1.51 preintervention to 2.04 postintervention (p = 0.005). Respondents rated the information received during handoff higher postintervention (2.12 vs. 2.52, p = 0.04). Compliance with screening for referral to the ED was 84.0%. The proportion of patients LWBS after referral decreased by 6.2 percentage points (p < 0.001). CONCLUSION: Using RDH in conjunction with a standardized triage screening may improve quality of information shared during this vulnerable transition and may assist in reduction of referred patients LWBS. The RDH process should be adapted into everyday workflow to ensure sustainability and effectiveness.

The importance of language in describing concussions: A qualitative analysis.

BACKGROUND: Concussions are mild traumatic brain injuries that are often undiagnosed due to difficulties in identifying symptoms. To minimize the negative sequelae associated with undiagnosed concussion, efforts have targeted improving concussion reporting. However, knowing more about concussions does not indicate how likely an athlete is to report their concussion. Alternatively, the attitudes and beliefs of athletes and surrounding stakeholders have shown to be a better indication of whether an athlete intends to report their concussion. Prior research has shown that athletes report concussions less often when the injury is described using language that minimizes their severity, such as when it is referred to as a "ding." This study evaluated whether describing concussions using the word "brain" was associated with individuals' underlying attitudes and beliefs about the injury's severity. OBJECTIVE: To measure the relationship between perceived concussion severity and the language used to describe concussions, specifically whether participants used the word "brain" in describing the injury. METHODS: One-on-one semi-structured telephone interviews were conducted, and a cross sectional secondary qualitative analysis was performed to assess participants' perceived concussion severity and their use of the word "brain" to describe concussions. DESIGN: Cross-sectional secondary qualitative analysis. SETTING: One-on-one semistructured telephone interviews. PARTICIPANTS: In 2017, 94 individuals involved in high school sports, including athletes, coaches, educators, parents of athletes, and athletic directors were recruited via convenience sampling. MAIN OUTCOME MEASURES: Respondents' perceived severity of concussions. RESULTS: Individuals who used a brain phrase to describe concussion also perceived concussions as more severe (p < .001). Specifically, those who described concussions with maximum severity had higher odds of using brain phrases than those who described concussions as having minimum (odds ratio [OR] = 0.05, 95% confidence interval [CI] = 0.002-0.299, p < .001) or moderate severity (OR = 0.24, 95% CI = 0.086-0.647, p = .003), with the most significant relationship found among coaches. CONCLUSIONS: These findings demonstrate the relationship between medical terminology and perceived severity of concussions. This relationship may play a role in concussion reporting behavior for coaches, athletes, and parents. Education programs using similar medical terminology may promote concussion reporting behaviors.

Patients do not recall important details about polyps, required for colorectal cancer prevention.

BACKGROUND & AIMS: Guidelines recommend that the age of initiation and frequency of colorectal cancer screening or surveillance be based on patients' personal and family histories of colorectal neoplasia. However, it is not clear whether patients accurately recall results from their colonoscopy examinations or features of specific polyps. METHODS: Between 2008 and 2011, a 35-question survey was given to outpatients at the Digestive Disease Institute at the Cleveland Clinic who had previously undergone colonoscopy there. We collected responses from 233 participants (mean age, 59 y; 49% male); they provided demographic information, along with responses to questions on past colonoscopies, personal and family history of colorectal neoplasia, detection of polyps by colonoscopy, and number and other key features of polyps detected. Patient responses were compared with medical records. RESULTS: Of the patients surveyed, 82% correctly recalled the presence or absence of polyp(s). Of the 118 who correctly reported having polyps, 61% correctly recalled the number, 26% recalled the size, and 6%-33% recalled features of polyp pathology. Only 8% of individuals correctly recalled all 3 key features of polyps (size, number, and pathology). The patients' age when they underwent colonoscopy, current age, sex, education, or method by which they received their colonoscopy results did not significantly affect the accuracy with which they recalled the presence or key features of polyps. CONCLUSIONS: Eighty-two percent of patients examined by colonoscopy correctly recalled whether or not they had polyp(s). However, most patients did not recall key details about their polyps (number, size, or pathology features) required to establish appropriate screening and surveillance intervals. New tools are needed to ensure that patients understand the importance of their colonoscopy findings and improve their recall accuracy.

Young adult daughters of BRCA1/2 positive mothers: what do they know about hereditary cancer and how much do they worry?

OBJECTIVE: The objectives of this study are to determine (i) what daughters, ages 18-24 years, of BRCA1/2 mutation carriers understand about their 50% chance of carrying a BRCA1/2 mutation and about risk reduction or management options for mutation carriers, (ii) the extent and nature of daughters' cancer-related distress, and (iii) the effects of knowing mother's mutation status on daughters' future plans. METHODS: A total of 40 daughters, currently aged 18-24 years, of mothers who tested positive for a mutation in BRCA1/2 were invited by mail to participate (with contact information supplied by their mothers). Daughters participated in a qualitative telephone interview about the impact of learning their mother's mutation status on their understanding of their own cancer risks and their cancer-related distress, and their knowledge of screening strategies, risk-reducing surgery, current health status, and future plans. Participants also completed study-specific demographic and family history questionnaires, the Brief Symptom Inventory-18, Impact of Event Scale (with hereditary predisposition to breast/ovarian cancer as the event), and the Breast Cancer Genetic Counseling Knowledge Questionnaire. RESULTS: Daughters' genetic knowledge is suboptimal; gaps and misconceptions were common. Over 1/3 of the daughters reported high cancer-related distress, despite normal levels of general distress. Disclosed genetic information raised future concerns, especially regarding childbearing. CONCLUSION: Targeted professional attention to this high-risk cohort of young women is critical to inform the next generation of daughters of BRCA1/2 mutation carriers and encourage recommended screening by age 25 years. Improved uptake of screening and risk reduction options could improve survival, and psychoeducation could reduce cancer-related distress.

Talking to children about maternal BRCA1/2 genetic test results: a qualitative study of parental perceptions and advice.

Family communication is the primary, initial means of educating the next, at-risk generation about hereditary cancer risk. In this study, in-depth parent narratives provided self-report of motivations, planning, satisfactions and regrets associated with sharing or not sharing maternal BRCA1/2 test results with young children and advice for parents considering disclosure and for genetic counselors. Interviews were conducted with 32 mothers tested for BRCA1/2 with children ages 8-21 years and 24 of their co-parents; interview narratives were analyzed qualitatively. Parents were concerned with both protecting and educating children about hereditary cancer risk. They expressed confidence that parents can constructively convey genetic information to minor children. Telling relieved most parents and satisfied a sense of parental duty. Parents strongly advised child-specific, age-appropriate tailoring of genetic information and emphasized conveying the positive, preventive utility of genetic information to children. Immunizing effects of disclosure were viewed as providing forewarning about and preparation for possible later family cancer diagnoses. Parents choosing not to tell children were advised to consider future disclosure. Narratives about parental sharing of BRCA1/2 test results with minor children support the feasibility of parental discussion of maternal genetic test results to the next at-risk generation. Results suggest development of intervention tools for parents would support decision-making and family communication and potentially reduce parental worry and regret. Recommendations are made for more active involvement by genetic counselors with tested parents around the topic of delivery of genetic information to children.

Results of a randomized controlled trial of a decision support intervention for disclosing maternal BRCA genetic test results to children and adolescents.

Objective: Evaluate the impact of a targeted family communication intervention for mothers undergoing genetic counseling and testing (GCT) for BRCA gene alterations. Methods: Following BRCA GCT, mothers (N = 204; M age = 45 y) were randomized to either a control condition (self-help print materials) or intervention (printed decision support guide, based on behavioral decision making theory in health care) for supporting choices about disclosing maternal genetic test results to children and adolescents. Behavioral assessments were administered prior to maternal GCT and after receipt of results: primary outcomes were maternal disclosure to children and parent-child communication quality. Results: Mothers in the intervention were > 2x likely to disclose their BRCA test results to their children compared to those in the control condition (odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.06, 5.10; p = .04). This effect was moderated by children's ages: mothers of preteens (<13 y) assigned to the intervention were >3x likely to disclose their results (OR = 3.74, 95% CI = 1.49, 9.41; p = .005). In adjusted models, intervention was also associated with favorable changes in the quality of parent-child communication (95% CI = 0.30, 9.00; p < .05). Conclusion: Decision support improves parent-child communication outcomes about GCT for hereditary breast-ovarian cancer. Innovation: This trial is among the first to empirically evaluate the outcomes of a behavioral intervention to support family communication of maternal BRCA risk information to children.

Biphasic gene expression changes elicited by Phakopsora pachyrhizi in soybean correlate with fungal penetration and haustoria formation.

Inoculation of soybean (Glycine max) plants with Phakopsora pachyrhizi, the causal organism of Asian soybean rust, elicits a biphasic response characterized by a burst of differential gene expression in the first 12 h. A quiescent period occurs from 24 to 48 h after inoculation, in which P. pachyrhizi continues to develop but does not elicit strong host responses, followed by a second phase of intense gene expression. To correlate soybean responses with P. pachyrhizi growth and development, we inoculated the soybean cultivar Ankur (accession PI462312), which carries the Rpp3 resistance gene, with avirulent and virulent isolates of P. pachyrhizi. The avirulent isolate Hawaii 94-1 elicits hypersensitive cell death that limits fungal growth on Ankur and results in an incompatible response, while the virulent isolate Taiwan 80-2 grows extensively, sporulates profusely, and produces a compatible reaction. Inoculated leaves were collected over a 288-h time course for microarray analysis of soybean gene expression and microscopic analysis of P. pachyrhizi growth and development. The first burst in gene expression correlated with appressorium formation and penetration of epidermal cells, while the second burst of gene expression changes followed the onset of haustoria formation in both compatible and incompatible interactions. The proliferation of haustoria coincided with the inhibition of P. pachyrhizi growth in the incompatible interaction or the beginning of accelerated growth in the compatible interaction. The temporal relationships between P. pachyrhizi growth and host responses provide an important context in which to view interacting gene networks that mediate the outcomes of their interactions.

Informed or anxious: patient preferences for release of test results of increasing sensitivity on electronic patient portals.

Worldwide, governments and healthcare systems are moving towards increased transparency to improve care quality, increase patient engagement, and decrease costs. For example, the American 21st Century Cures Act Final Rule requires providers to grant patients access to their electronic medical record. Unfortunately, limited research guides release of test results to online patient portals, especially concerning emotionally sensitive information. To address this gap, we surveyed the largest patient sample published to date. This cross-sectional survey project was conducted by the Market Research & Insights and Office of Patient Experience departments at a large academic medical center. Data were analyzed in SPSS using descriptive statistics and Z-tests. Of 8030 respondents, 74% and 57% accepted first learning their results online for cholesterol and strep throat tests, respectively. Most prefer in-person appointments for more serious tests detecting cancer (54%) and fetal miscarriage (53%). Excluding sexually transmitted disease (STD) testing, there are no clinically significant differences in preference between respondents previously diagnosed with the condition in question and respondents without such experience. When weighing the possibility of a 3-week wait to hear from their provider, most patients want automatic release of cholesterol (94%), strep throat (90%), genetic (68%), and STD (60%) test results, but the majority say it is unacceptable to receive Alzheimer's (52%), fetal miscarriage (51%), and cancer (59%) test results this way. Electronic results release is acceptable for less serious tests, but not for more consequential tests. Providers should consider patient preferences when developing policies to increase healthcare transparency. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12553-021-00628-5.

Long-Term Adaptation Among Adolescent and Young Adult Children to Familial Cancer Risk.

BACKGROUND: It is important to examine adolescent and young adult (AYA) children's long-term psychosocial and behavioral adaptation to disclosure of maternal BRCA-positive carrier status (BRCA+) to inform approaches for familial cancer risk communication, education, and counseling. METHODS: Mothers underwent BRCA genetic testing 1 to 5 years earlier. Group differences in AYAs' self-reported outcomes were analyzed by maternal health and carrier status, and child age and sex. RESULTS: A total of N = 272 AYAs were enrolled: 76.1% of their mothers were breast or ovarian cancer survivors and 17.3% were BRCA+. AYAs' cancer risk behavior (tobacco and alcohol use, physical activity) and psychologic distress levels did not vary by maternal status. In bivariate analyses, AYAs of cancer-surviving mothers believed themselves to be at greater risk for, and were more knowledgeable about, cancer than AYAs of mothers without cancer. AYAs of BRCA+ mothers were more concerned about cancer, held stronger beliefs about genetic risk, and placed a higher value on learning about genetics. In adjusted models, maternal cancer history (not BRCA+) remained associated with AYAs' greater perceptions of cancer risk (P = .002), and knowledge about cancer (P = .03) and its causes (P = .002). CONCLUSIONS: Disclosing maternal BRCA+ status did not influence children's lifestyle behavior or adversely affect quality of life long term. AYAs of BRCA+ mothers were more aware of and interested in genetic risk information. Such families may benefit from support to promote open communication about genetic testing choices.

Clinical Impact of Pathogenic Variants in DNA Damage Repair Genes beyond BRCA1 and BRCA2 in Breast and Ovarian Cancer Patients.

Consensus guidelines for hereditary breast and ovarian cancer include management recommendations for pathogenic/likely pathogenic (P/LP) variants in ATM, CHEK2, PALB2, and other DNA damage repair (DDR) genes beyond BRCA1 or BRCA2. We report on clinical management decisions across three academic medical centers resulting from P/LP findings in DDR genes in breast/ovarian cancer patients. Among 2184 patients, 156 (7.1%) carried a P/LP variant in a DDR gene. Clinical follow-up information was available for 101/156 (64.7%) patients. Genetic test result-based management recommendations were made for 57.8% (n = 59) of patients and for 64.7% (n = 66) of patients' family members. Most recommendations were made for moderate-to-high risk genes and were consistent with guidelines. Sixty-six percent of patients (n = 39/59) implemented recommendations. This study suggests that P/LP variants in DDR genes beyond BRCA1 and BRCA2 can change clinical management recommendations for patients and their family members, facilitate identification of new at-risk carriers, and impact treatment decisions. Additional efforts are needed to improve the implementation rates of genetic-testing-based management recommendations for patients and their family members.

Gastric cancer in individuals with Li-Fraumeni syndrome.

PURPOSE: Li-Fraumeni syndrome is a rare hereditary cancer syndrome associated with germline mutations in the TP53 gene. Although sarcomas, brain tumors, leukemias, breast and adrenal cortical carcinomas are typically recognized as Li-Fraumeni syndrome-associated tumors, the occurrence of gastrointestinal neoplasms has not been fully evaluated. In this analysis, we investigated the frequency and characteristics of gastric cancer in Li-Fraumeni syndrome. METHODS: Pedigrees and medical records of 62 TP53 mutation-positive families were retrospectively reviewed from the Dana-Farber/National Cancer Institute Li-Fraumeni syndrome registry. We identified subjects with gastric cancer documented either by pathology report or death certificate and performed pathology review of the available specimens. RESULTS: Among 62 TP53 mutation-positive families, there were 429 cancer-affected individuals. Gastric cancer was the diagnosis in the lineages of 21 (4.9%) subjects from 14 families (22.6%). The mean and median ages at gastric cancer diagnosis were 43 and 36 years, respectively (range: 24-74 years), significantly younger compared with the median age at diagnosis in the general population based on Surveillance Epidemiology and End Results data (71 years). Five (8.1%) families reported two or more cases of gastric cancer, and six (9.7%) families had cases of both colorectal and gastric cancers. No association was seen between phenotype and type/location of the TP53 mutations. Pathology review of the available tumors revealed both intestinal and diffuse histologies. CONCLUSIONS: Early-onset gastric cancer seems to be a component of Li-Fraumeni syndrome, suggesting the need for early and regular endoscopic screening in individuals with germline TP53 mutations, particularly among those with a family history of gastric cancer.

Pathogenicity of VHL variants in families with non-syndromic von Hippel-Lindau phenotypes: An integrated evaluation of germline and somatic genomic results.

Von Hippel-Lindau (VHL) syndrome is a hereditary tumor syndrome associated with germline loss-of-function pathogenic variants (PVs) in the VHL gene. VHL is classically associated with a high penetrance for many different tumor types. The same tumors may be sporadic in the setting of somatic VHL PVs. With more large-scale genome sequencing, variants with low penetrance or variable expressivity are identified. This has introduced challenges in patient management and the clinical interpretation of germline VHL variants identified in non-classic families. Herein, we report individuals from 3 non-classic families with VHL variants who presented with unexpected or non-syndromic phenotypes, but often with a VHL component tumor. In family 1, two siblings, age 61, with pathogenic VHL p.Leu188Val presented with clear cell renal cell carcinoma and lobular breast cancer. In family 2, the proband, age 82, was found to have pathogenic germline VHL p.Tyr98His on testing for metastatic bladder cancer. In family 3, four members carried germline VHL p.Pro81Ser (variant of uncertain significance), after the proband, age 40, presented with cerebellar hemangioblastoma. None of the individuals in the above three families met clinical criteria of classic VHL, suggesting germline VHL p.Leu188Val, p.Y98H, and p.Tyr98His may be low penetrant variants. Large studies are needed to evaluate penetrance and possible effect of genetic and non-genetic modifiers. Somatic sequencing performed on their respective tumors could help discern the etiology of the component tumors, highlighting the role of somatic evaluation in these cases. Paired examination of somatic and germline findings provided a more complete landscape of genome alterations in cancer development.

Fully Actuated Body-Mounted Robotic System for MRI-Guided Lower Back Pain Injections: Initial Phantom and Cadaver Studies.

This paper reports the improved design, system integration, and initial experimental evaluation of a fully actuated body-mounted robotic system for real-time MRI-guided lower back pain injections. The 6-DOF robot is composed of a 4-DOF needle alignment module and a 2-DOF remotely actuated needle driver module, which together provide a fully actuated manipulator that can operate inside the scanner bore during imaging. The system minimizes the need to move the patient in and out of the scanner during a procedure, and thus may shorten the procedure time and streamline the clinical workflow. The robot is devised with a compact and lightweight structure that can be attached directly to the patient's lower back via straps. This approach minimizes the effect of patient motion by allowing the robot to move with the patient. The robot is integrated with an image-based surgical planning module. A dedicated clinical workflow is proposed for robot-assisted lower back pain injections under real-time MRI guidance. Targeting accuracy of the system was evaluated with a real-time MRI-guided phantom study, demonstrating the mean absolute errors (MAE) of the tip position to be 1.50±0.68mm and of the needle angle to be 1.56±0.93°. An initial cadaver study was performed to validate the feasibility of the clinical workflow, indicating the maximum error of the position to be less than 1.90mm and of the angle to be less than 3.14°.

Structure-property studies of an imidazoquinoline chemotype with antitrypanosomal activity.

Human African trypanosomiasis is a neglected tropical disease (NTD) that is fatal if left untreated. Although approximately 13 million people live in moderate- to high-risk areas for infection, current treatments are plagued by problems with safety, efficacy, and emerging resistance. In an effort to fill the drug development pipeline for HAT, we have expanded previous work exploring the chemotype represented by the compound NEU-1090, with a particular focus on improvement of absorption, distribution, metabolism and elimination (ADME) properties. These efforts resulted in several compounds with substantially improved aqueous solubility, although these modifications typically resulted in a loss of trypanosomal activity. We herein report the results of our investigation into the antiparasitic activity, toxicity, and ADME properties of this class of compounds in the interest of informing the NTD drug discovery community and avoiding duplication of effort.