Timing of genetic testing in BRCA1/2 and PALB2-Associated breast cancer: Preoperative result disclosure increases uptake of risk-reducing mastectomy and reduces unnecessary exposure to radiotherapy.

INTRODUCTION: The impact of timing of genetic testing on uptake of risk reducing mastectomy (RRM) in affected female BRCA1/2 or PALB2 carriers remains an area of evolving interest, particularly with the introduction of mainstream genetic testing initiatives. METHODS: Women with stage I-III breast cancer and a confirmed germline pathogenic variant in BRCA1/2 or PALB2 between 2000 and 2023 were identified from an institutional genetics database. Uptake of RRM was evaluated according to disclosure of genetic testing results before or after index surgery for a first diagnosis of breast cancer. RESULTS: The cohort included 287 female BRCA1/2 or PALB2 carriers with a median age of 44 years (IQR, 36-52). Overall, 155 (54 %) carriers received genetic testing results before and 132 (46 %) after index breast surgery. Receipt of genetic testing results before surgery was associated with a higher rate of index bilateral mastectomy (58.7 % vs. 7.6 %, p < 0.001) and a commensurate decrease in adjuvant radiation (41.9 % vs. 74.2 %, p < 0.001). At a median follow up of 4.4 years after genetic testing, 219 (76.3 %) affected carriers had undergone bilateral RRM, including 83.9 % with preoperative knowledge and 67.4 % of patients with postoperative knowledge of their germline pathogenic variant (log rank, p < 0.001). On multivariate regression, disclosure of genetic testing results before index breast surgery was independently associated with long-term uptake of bilateral mastectomy (HR 1.69, 95 % CI 1.21-2.38). CONCLUSION: Genetic testing results delivered prior to index breast surgery increase uptake of bilateral RRM in affected BRCA1/2 and PALB2 carriers. Efforts to mainstream genetic testing would help optimize surgical decision-making.

Supporting parents while their child is receiving neurocritical care.

The post-intensive care syndrome (PICS) concept whereby the ICU experience of the patient as well as their family can have long-term deleterious health outcomes in both the patient and the family provides a rationale and impetus for modifying the ICU experience for the parents of patients receiving pediatric neurocritical care. This article uses the PICS framework to provide insight to that parental experience. Included are the words of parents who tell what they felt and what they most needed from their children's doctors while their children were receiving neurocritical care. Based on their and many other ICU parents' advice and the PICS research, we identify a short list of specific steps the medical team can take immediately to support these parents.

Surgical Decision Making in Genetically High-Risk Women: Quantifying Postoperative Complications and Long-Term Risks of Supplemental Surgery After Risk-Reducing Mastectomy.

BACKGROUND: Risk-reducing mastectomy (RRM) helps prevent breast cancer in high-risk women but also carries a risk of unanticipated supplemental surgeries. We sought to determine the likelihood of supplemental surgeries following RRM. METHODS: We performed a retrospective cohort study of female patients with a confirmed germline pathogenic variant (GPV) in a breast cancer susceptibility gene (BRCA1/2, PALB2 and others) who underwent bilateral or contralateral RRM at our institution between 2006 and 2022. Supplemental surgeries were defined as any operation requiring general or local anesthesia performed outside of the initially planned procedure(s). The Kaplan-Meier method was used to estimate the 5-years cumulative incidence of supplemental surgery. RESULTS: Of 560 GPV carriers, RRMs were performed in 258 (46.1%) women. The median age of the cohort was 44 years (interquartile range 37-52 years), with 33 (12.8%) patients undergoing RRM without reconstruction and 225 (87.2%) undergoing RRM with reconstruction. Following surgery, 34 patients (13.2%) developed early (< 30 days) postoperative complications, including infection, hematoma, seroma, loss of the nipple areola complex, flap necrosis, implant exposure and/or prosthesis removal. At a median follow-up of 3.8 years, 94 (36.4%) GPV carriers underwent at least one reoperation. Participants who experienced an early postoperative complication had the highest rate of reoperation (85.3% vs. 29.0%; p < 0.001) and a significantly higher likelihood of multiple additional surgical interventions (41.2% vs. 10.7%; p < 0.001). The 5-years rate of supplemental surgery was 39.2% [95% confidence interval (CI) 32.7-46.5] in the overall cohort and 31.5% (95% CI 24.9-39.3) in patients without an early postoperative complication. CONCLUSIONS: Unanticipated supplemental surgeries occur in 40% of GPV carriers following RRM and in nearly one-third of patients without early postoperative complications.

Forward with Dementia: process evaluation of an Australian campaign to improve post-diagnostic support.

BACKGROUND: Forward with Dementia is a co-designed campaign to improve communication of dementia diagnosis and post-diagnostic support. METHODS: Webinars, a website, social and traditional media, and promotions through project partners were used to disseminate campaign messages to health and social care professionals (primary audience) and people with dementia and carers (secondary audience). The campaign ran between October 2021 and June 2022, with 3-months follow-up. The RE-AIM framework was used for process evaluation. Measurements included surveys and interviews, a log of activities (e.g. webinars, social media posts) and engagements (e.g. attendees, reactions to posts), and Google Analytics. RESULTS: There were 29,053 interactions with campaign activities. More than three-quarters of professionals (n = 63/81) thought webinars were very or extremely helpful. Professionals and people with dementia and carers reported that the website provided appropriate content, an approachable tone, and was easy to use. Following campaign engagement, professionals planned to (n = 77/80) or had modified (n = 29/44) how they communicated the diagnosis and/or provided post-diagnostic information and referrals. Qualitative data suggested that the campaign may have led to benefits for some people with dementia and carers. CONCLUSIONS: Forward with Dementia was successful in terms of reach, appropriateness, adoption and maintenance for professionals, however flow-through impacts on people with dementia are not clear. Targeted campaigns can potentially change health professionals' communication and support around chronic diseases such as dementia.

Germline EGFR c.2527G > A (p.V843I) variant and familial lung cancer.

BACKGROUND: Somatic epidermal growth factor receptor (EGFR) pathogenic variants have been identified and are routinely tested in the molecular diagnosis of non-small cell lung cancer (NSCLC) as they represent a target for EGFR tyrosine kinase inhibitor (TKI) therapy. However, germline variants in EGFR are much less frequently reported. CASE PRESENTATION: Herein, we report the case of a 46-year-old woman diagnosed with lung adenocarcinoma who was found to harbor a rare germline missense variant in exon 21 of EGFR: NM_005228.5(EGFR):c.2527G>A (p.V843I). In the tumor, this variant (Cosmic ID COSV51767379) was accompanied by a secondary, known pathogenic EGFR variant in cis, also occurring in exon 21, c.2573T>G (p.L858R) (Cosmic ID 6224). Her mother was previously diagnosed with poorly differentiated lung carcinoma and her tumor was also found to harbour the p.V843I variant but no other pathogenic variants. Notably, the proband's sister, diagnosed with a lung carcinoma with sarcomatous features at age 44, did not carry this variant or any other somatic or germline EGFR variants. CONCLUSION: This is the second report of familial lung adenocarcinoma associated with the germline p.V843I variant, which remains classified as a variant of uncertain significance. The lack of segregation of this variant in the proband's affected sister illustrates the complexity with evaluating lung cancer predisposition factors. Currently, there is a paucity of data regarding the therapeutic outcomes of patients with tumors expressing this rare germline variant, therefore we propose an algorithm for the identification of at-risk individuals and families as the first step for their personalized management.

Surviving status epilepticus: The patient and family perspective.

Awareness of the long-term outcomes of status epilepticus is key to understanding the condition overall. Maintaining ties with patients' families is vital to both obtaining better long-term patient outcomes and obtaining that elusive data on long-term conditions. Common language and linked infrastructure support these ties. This position is posed within the context of NORSE (new-onset refractory status epilepticus) and FIRES (febrile infection-related epilepsy syndrome). This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

Incidence of Occult Breast Cancer in Carriers of BRCA1/2 or Other High-Penetrance Pathogenic Variants Undergoing Prophylactic Mastectomy: When is Sentinel Lymph Node Biopsy Indicated?

BACKGROUND: This study sought to determine the likelihood of occult malignancy during risk-reducing mastectomy in high-penetrance pathogenic variant carriers to help refine axillary staging recommendations. METHODS: The authors performed a retrospective cohort study analyzing all female carriers of pathogenic variants in BRCA1/2, PALB2 or other genes who underwent prophylactic surgery at their institution between 2006 and 2021. Occult breast cancer was defined as the unanticipated presence of in situ or invasive malignancy on pathologic evaluation of prophylactic mastectomy specimens. RESULTS: Of 523 women, 243 carriers met the inclusion criteria for the study including 124 BRCA1 (51.0%), 108 BRCA2 (44.4%), and 11 PALB2, TP53, CDH1, or PTEN (4.6%) carriers. The median age was 44 years (interquartile range, 37-52 years). Overall, 128 women (52.7%) underwent bilateral prophylactic mastectomies, and 115 (47.3%) underwent contralateral prophylactic mastectomy. In the 371 mastectomies performed, 16 (4.3%) occult malignancies were diagnosed. Most of the occult malignancies were ductal carcinoma in situ (13 mastectomies, 3.5%), whereas 3 mastectomies (0.8%) contained invasive breast cancer. If Breast Imaging Reporting and Data System (BIRADS) 1-2 or BIRADS 3 findings were reported on preoperative magnetic resonance imaging (MRI), the rate of occult malignancy decreased to 3.0 and 2.8%, respectively, per mastectomy. The patient-level factors associated with a likelihood of occult breast cancer greater than 10% included a history of prior breast cancer, age exceeding 60 years, and BIRADS 4 findings on preoperative imaging. CONCLUSIONS: Occult invasive malignancy was detected in less than 1% of the risk-reducing mastectomies performed for women with BRCA1/2 or PALB2 pathogenic variants. Sentinel lymph node biopsy can be safely avoided when BIRADS 1-3 findings are reported on preoperative MRI.

How to Help Your Patients Enroll in the New-Onset Refractory Status Epilepticus (NORSE) and Febrile Infection-Related Epilepsy Syndrome (FIRES) Family Registry, and Other Rare Epilepsy Registries.

New-onset refractory status epilepticus (NORSE) is a rare clinical presentation of refractory status epilepticus (RSE) that occurs in people without active epilepsy or preexisting neurologic disorder. Febrile infection-related epilepsy syndrome (FIRES) is a subcategory of NORSE. New-onset refractory status epilepticus/FIRES are becoming increasingly recognized; however, information pertaining to disease course, clinical outcomes, and survivorship remains limited, and mortality and morbidity are variable, but often high. The objective of the NORSE/FIRES Family Registry is to (1) provide an easily accessible and internationally available multilingual registry into which survivors or NORSE/FIRES surrogates or family members of people affected by NORSE/FIRES or their physicians can enter data in a systematic and rigorous research study from anywhere in the world where internet is available; and (2) to examine past medical history, outcomes, and quality of life for people affected by NORSE/FIRES.

MealTime-MS: A Machine Learning-Guided Real-Time Mass Spectrometry Analysis for Protein Identification and Efficient Dynamic Exclusion.

Mass spectrometry-based proteomics technologies are prime methods for the high-throughput identification of proteins in complex biological samples. Nevertheless, there are still technical limitations that hinder the ability of mass spectrometry to identify low abundance proteins in complex samples. Characterizing such proteins is essential to provide a comprehensive understanding of the biological processes taking place in cells and tissues. Still today, most mass spectrometry-based proteomics approaches use a data-dependent acquisition strategy, which favors the collection of mass spectra from proteins of higher abundance. Since the computational identification of proteins from proteomics data is typically performed after mass spectrometry analysis, large numbers of mass spectra are typically redundantly acquired from the same abundant proteins, and little to no mass spectra are acquired for proteins of lower abundance. We therefore propose a novel supervised learning algorithm, MealTime-MS, that identifies proteins in real-time as mass spectrometry data are acquired and prevents further data collection from confidently identified proteins to ultimately free mass spectrometry resources to improve the identification sensitivity of low abundance proteins. We use real-time simulations of a previously performed mass spectrometry analysis of a HEK293 cell lysate to show that our approach can identify 92.1% of the proteins detected in the experiment using 66.2% of the MS2 spectra. We also demonstrate that our approach outperforms a previously proposed method, is sufficiently fast for real-time mass spectrometry analysis, and is flexible. Finally, MealTime-MS' efficient usage of mass spectrometry resources will provide a more comprehensive characterization of proteomes in complex samples.

Effects of concentrated poultry operations and cropland manure application on antibiotic resistant Escherichia coli and nutrient pollution in Chesapeake Bay watersheds.

Manure from poultry operations is typically applied to nearby cropland and may affect nutrient loading and the spread of antibiotic resistance (ABR). We analyzed the concentrations of nitrogen and phosphorus and the occurrence of ABR in Escherichia coli (E. coli) and extra-intestinal pathogenic E. coli isolates from streams draining 15 small (<19 km2) watersheds of the Chesapeake Bay with contrasting levels of concentrated poultry operations. Total nitrogen and nitrate plus nitrite concentrations increased with poultry barn density with concentrations two and three times higher, respectively, in watersheds with the highest poultry barn densities compared to those without poultry barns. Analysis of N and O isotopes in nitrate by mass spectrometry showed an increase in the proportion of 15N associated with an increase in barn density, suggesting that the nitrate associated with poultry barns originated from manure. Phosphorus concentrations were not correlated with barn density. Antibiotic susceptibility testing of putative E. coli isolates was conducted using the disk diffusion method for twelve clinically important antibiotics. Of the isolates tested, most were completely susceptible (67%); 33% were resistant to at least one antibiotic, 24% were resistant to ampicillin, 13% were resistant to cefazolin, and 8% were multi-drug resistant. Resistance to three cephalosporin drugs was positively associated with an index of manure exposure estimated from poultry barn density and proportion of cropland in a watershed. The proportion of E. coli isolates resistant to cefoxitin, cefazolin, and ceftriaxone, broad-spectrum antibiotics important in human medicine, increased by 18.9%, 16.9%, and 6.2%, respectively, at the highest estimated level of manure exposure compared to watersheds without manure exposure. Our results suggest that comparisons of small watersheds could be used to identify geographic areas where remedial actions may be needed to reduce nutrient pollution and the public health risks of ABR bacteria.

Strategic Priorities for Research on Antibiotic Alternatives in Animal Agriculture-Results From an Expert Workshop.

The emergence, spread, and expansion of antibiotic resistance and increasing restrictions on the use of antibiotics in animal agriculture have created a need for efficacious alternatives that remains unmet. Prioritizing research needs in the development of alternatives is key to ensuring that scarce research resources are dedicated to the most promising approaches. However, frameworks to enable a consistent, systematic, and transparent evaluation of antibiotic alternative candidates are lacking. Here, we present such an evaluation framework.

Communication Challenges: A Spotlight on New-Onset Refractory Status Epilepticus.

New-onset refractory status epilepticus (NORSE) is a rare, potentially devastating condition that occurs abruptly in previously healthy patients of any age but most commonly in children and young adults. It has an unpredictable clinical course requiring immediate, often prolonged, critical care support with multiple specialists involved and frequently results in severe life-altering sequelae or death. Communication in NORSE is challenging because its etiology in a given patient is initially unknown (and often remains so), the clinical course and outcome are unpredictable, and many health care team members are involved in the care of a patient. We address the communication challenges seen in NORSE through proactive communication on 3 levels: (1) in the shared decision-making process with the family, (2) within an individual hospital, and (3) across institutions. Intentional organizational change and enhanced information dissemination may help break down barriers to effective communication. Key initiatives for enhancing information dissemination in NORSE are (1) the identification of a most responsible physician to integrate information from subspecialties, to communicate frequently and candidly with the family, and to provide continuity of care over a prolonged period of time and (2) the early involvement of palliative care services alongside ongoing therapies with curative intent to support families and the medical team in decision making and communication.

Vaccines as alternatives to antibiotics for food producing animals. Part 1: challenges and needs.

Vaccines and other alternative products can help minimize the need for antibiotics by preventing and controlling infectious diseases in animal populations, and are central to the future success of animal agriculture. To assess scientific advancements related to alternatives to antibiotics and provide actionable strategies to support their development, the United States Department of Agriculture, with support from the World Organisation for Animal Health, organized the second International Symposium on Alternatives to Antibiotics. It focused on six key areas: vaccines; microbial-derived products; non-nutritive phytochemicals; immune-related products; chemicals, enzymes, and innovative drugs; and regulatory pathways to enable the development and licensure of alternatives to antibiotics. This article, part of a two-part series, synthesizes and expands on the expert panel discussions regarding opportunities, challenges and needs for the development of vaccines that may reduce the need for use of antibiotics in animals; new approaches and potential solutions will be discussed in part 2 of this series. Vaccines are widely used to prevent infections in food animals. Various studies have demonstrated that their animal agricultural use can lead to significant reductions in antibiotic consumption, making them promising alternatives to antibiotics. To be widely used in food producing animals, vaccines have to be safe, effective, easy to use, and cost-effective. Many current vaccines fall short in one or more of these respects. Scientific advancements may allow many of these limitations to be overcome, but progress is funding-dependent. Research will have to be prioritized to ensure scarce public resources are dedicated to areas of potentially greatest impact first, and private investments into vaccine development constantly compete with other investment opportunities. Although vaccines have the potential to improve animal health, safeguard agricultural productivity, and reduce antibiotic consumption and resulting resistance risks, targeted research and development investments and concerted efforts by all affected are needed to realize that potential.

Vaccines as alternatives to antibiotics for food producing animals. Part 2: new approaches and potential solutions.

Vaccines and other alternative products are central to the future success of animal agriculture because they can help minimize the need for antibiotics by preventing and controlling infectious diseases in animal populations. To assess scientific advancements related to alternatives to antibiotics and provide actionable strategies to support their development, the United States Department of Agriculture, with support from the World Organisation for Animal Health, organized the second International Symposium on Alternatives to Antibiotics. It focused on six key areas: vaccines; microbial-derived products; non-nutritive phytochemicals; immune-related products; chemicals, enzymes, and innovative drugs; and regulatory pathways to enable the development and licensure of alternatives to antibiotics. This article, the second part in a two-part series, highlights new approaches and potential solutions for the development of vaccines as alternatives to antibiotics in food producing animals; opportunities, challenges and needs for the development of such vaccines are discussed in the first part of this series. As discussed in part 1 of this manuscript, many current vaccines fall short of ideal vaccines in one or more respects. Promising breakthroughs to overcome these limitations include new biotechnology techniques, new oral vaccine approaches, novel adjuvants, new delivery strategies based on bacterial spores, and live recombinant vectors; they also include new vaccination strategies in-ovo, and strategies that simultaneously protect against multiple pathogens. However, translating this research into commercial vaccines that effectively reduce the need for antibiotics will require close collaboration among stakeholders, for instance through public-private partnerships. Targeted research and development investments and concerted efforts by all affected are needed to realize the potential of vaccines to improve animal health, safeguard agricultural productivity, and reduce antibiotic consumption and resulting resistance risks.

The Role of Hope, Compassion, and Uncertainty in Physicians' Reluctance to Initiate Palliative Care.

This article addresses whether physicians' close ties to their patients might play an unexamined role in their reluctance to initiate palliative care. In cases characterized by uncertainty, physicians' emotional investment in their patients and patients' families might unduly promote decisions to continue aggressive treatment rather than transition to comfort care. Continued evaluation and communication of patient status, including scheduled objective consultations, can align compassionate actions with patients' best interests. This argument and analysis are based on a case of new onset refractory status epilepticus (NORSE).

Evolution of genetic assessment for BRCA-associated gynaecologic malignancies: a Canadian multisociety roadmap.

The landscape of genetic testing in ovarian cancer patients has changed dramatically in recent years. The therapeutic benefits of poly ADP-ribose polymerase (PARP) inhibitors in treatment of BRCA1/2-related ovarian cancers has resulted in an increased demand and urgency for genetic testing results, while technological developments have led to widespread use of multi-gene cancer panels and development of tumour testing protocols. Traditional genetic counselling models are no longer sustainable and must evolve to match the rapid evolution of genetic testing technologies and developments in personalized medicine. Recently, representatives from oncology, clinical genetics, molecular genetics, pathology, and patient advocacy came together to create a national multi-disciplinary Canadian consortium. By aligning stakeholder interests, the BRCA Testing to Treatment (BRCA TtoT) Community of Practice aims to develop a national strategy for tumour and germline BRCA1/2 testing and genetic counselling in women with ovarian cancer. This article serves to provide an overview of the recent evolution of genetic assessment for BRCA1/2-associated gynecologic malignancies and outline a Canadian roadmap to facilitate change, improve genetic testing rates, and ultimately improve outcomes for hereditary ovarian cancer patients and their families.

New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives.

We report the proceedings of the First International new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) Symposium. To promote awareness of this condition and foster research efforts, we conveyed the First International new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) Symposium. The conference was supported by The NORSE Institute (http://www.norseinstitute.org). This article summarizes the discussions that were held during the Symposium and presents our strategy to unravel the cause of these disorders and to improve patient care. The standardized definitions for these disorders that have been developed, are required to improve communication and facilitate the development of multicenter registries and biobanks. A distinction between childhood- and adult-onset forms of the syndrome is not supported by strong scientific evidence and it is argued that both should be studied together. Although the pathophysiology remains elusive, nascent evidence suggests a role for a postinfectious cytokine-mediated mechanism, which should be further investigated. It also appears important to develop tools for their early recognition and prompt treatment. Recent evidence suggests that specific electroencephalography (EEG) features might be helpful. The optimal treatment options remain to be determined; immune therapies are usually disappointing, but the ketogenic diet has proved effective in uncontrolled trials. NORSE and FIRES represent a very delicate clinical situation with specific communication issues between physicians and with patients and families. Standardized consensus definitions and a multidisciplinary multicenter strategy will help research efforts and improve clinical care for patients with NORSE and FIRES.