Alpha herpesvirus exocytosis from neuron cell bodies uses constitutive secretory mechanisms, and egress and spread from axons is independent of neuronal firing activity.

Alpha herpesviruses naturally infect the peripheral nervous system, and can spread to the central nervous system, causing severe debilitating or deadly disease. Because alpha herpesviruses spread along synaptic circuits, and infected neurons exhibit altered electrophysiology and increased spontaneous activity, we hypothesized that alpha herpesviruses use activity-dependent synaptic vesicle-like regulated secretory mechanisms for egress and spread from neurons. Using live-cell fluorescence microscopy, we show that Pseudorabies Virus (PRV) particles use the constitutive Rab6 post-Golgi secretory pathway to exit from the cell body of primary neurons, independent of local calcium signaling. Some PRV particles colocalize with Rab6 in the proximal axon, but we did not detect colocalization/co-transport in the distal axon. Thus, the specific secretory mechanisms used for viral egress from axons remains unclear. To address the role of neuronal activity more generally, we used a compartmentalized neuron culture system to measure the egress and spread of PRV from axons, and pharmacological and optogenetics approaches to modulate neuronal activity. Using tetrodotoxin to silence neuronal activity, we observed no inhibition, and using potassium chloride or optogenetics to elevate neuronal activity, we also show no increase in virus spread from axons. We conclude that PRV egress from neurons uses constitutive secretory mechanisms: generally, activity-independent mechanisms in axons, and specifically, the constitutive Rab6 post-Golgi secretory pathway in cell bodies.

Novel stimuli evoke excess activity in the mouse primary visual cortex.

To explore how neural circuits represent novel versus familiar inputs, we presented mice with repeated sets of images with novel images sparsely substituted. Using two-photon calcium imaging to record from layer 2/3 neurons in the mouse primary visual cortex, we found that novel images evoked excess activity in the majority of neurons. This novelty response rapidly emerged, arising with a time constant of 2.6 ± 0.9 s. When a new image set was repeatedly presented, a majority of neurons had similarly elevated activity for the first few presentations, which decayed to steady state with a time constant of 1.4 ± 0.4 s. When we increased the number of images in the set, the novelty response's amplitude decreased, defining a capacity to store ∼15 familiar images under our conditions. These results could be explained quantitatively using an adaptive subunit model in which presynaptic neurons have individual tuning and gain control. This result shows that local neural circuits can create different representations for novel versus familiar inputs using generic, widely available mechanisms.

Responsiveness of Critically Ill Adults With Multimorbidity to Rehabilitation Interventions: A Patient-Level Meta-Analysis Using Individual Pooled Data From Four Randomized Trials.

OBJECTIVE: To explore if patient characteristics (pre-existing comorbidity, age, sex, and illness severity) modify the effect of physical rehabilitation (intervention vs control) for the coprimary outcomes health-related quality of life (HRQoL) and objective physical performance using pooled individual patient data from randomized controlled trials (RCTs). DATA SOURCES: Data of individual patients from four critical care physical rehabilitation RCTs. STUDY SELECTION: Eligible trials were identified from a published systematic review. DATA EXTRACTION: Data sharing agreements were executed permitting transfer of anonymized data of individual patients from four trials to form one large, combined dataset. The pooled trial data were analyzed with linear mixed models fitted with fixed effects for treatment group, time, and trial. DATA SYNTHESIS: Four trials contributed data resulting in a combined total of 810 patients (intervention n = 403, control n = 407). After receiving trial rehabilitation interventions, patients with two or more comorbidities had HRQoL scores that were significantly higher and exceeded the minimal important difference at 3 and 6 months compared with the similarly comorbid control group (based on the Physical Component Summary score (Wald test p = 0.041). Patients with one or no comorbidities who received intervention had no HRQoL outcome differences at 3 and 6 months when compared with similarly comorbid control patients. No patient characteristic modified the physical performance outcome in patients who received physical rehabilitation. CONCLUSIONS: The identification of a target group with two or more comorbidities who derived benefits from the trial interventions is an important finding and provides direction for future investigations into the effect of rehabilitation. The multimorbid post-ICU population may be a select population for future prospective investigations into the effect of physical rehabilitation.

Body Composition, Physical Function and Exercise Capacity in Chronic Obstructive Pulmonary Disease.

Current literature yields unequivocal results regarding the effect of body composition on physical function in patients with chronic obstructive pulmonary disease and disproportionately includes a majority of males. The purpose of this study was to determine whether specific body composition measures are significantly associated with physical function and exercise capacity in patients with chronic obstructive pulmonary disease with equal representation of males and females. Independent variables included sex, total body mass, total body lean and fat mass, appendicular total mass, and appendicular lean and fat mass. Dependent variables included peak oxygen consumption, 6-minute walk distance and self-reported physical function. Patients (n = 170) with dual-energy X-ray absorptiometry data, 6-minute walk distance, and self-reported physical function were used for these analyses. A sub-set of 145 of these patients with peak oxygen consumption data were also analysed. Hierarchical multiple regression analysis was used to determine if sex and body composition measures correlated with physical function and exercise capacity and if they explained additional variance after controlling for disease severity. After controlling for disease severity, appendicular lean mass, total body fat mass, and sex explained an additional 16.5% of the variance in peak oxygen consumption (p < 0.001). Appendicular lean mass explained an additional 8.9% of the variance in 6-minute walk distance (p < 0.001) and an additional 2.5% of the variance in self-reported physical function (p = 0.057). Body composition measures may further predict exercise capacity, 6-minute walk distance, and self-reported physical function in patients with chronic obstructive pulmonary disease.

Seasonality in surgical outcome data: a systematic review and narrative synthesis.

BACKGROUND: Seasonal trends in patient outcomes are an under-researched area in perioperative care. This systematic review evaluates the published literature on seasonal variation in surgical outcomes worldwide. METHODS: MEDLINE, Embase, Cochrane, CINHAL, and Web of Science were searched for studies on major surgical procedures, examining mortality or other patient-relevant outcomes, across seasonal periods up to February 2019. Major surgery was defined as a procedure requiring an overnight stay in an inpatient medical facility. We included studies exploring variation according to calendar and meteorological seasons and recurring annual events including staff turnover. Quality was assessed using an adapted Downs and Black scoring system. RESULTS: The literature search identified 82 studies, including 22 210 299 patients from four continents. Because of the heterogeneity of reported outcomes and literature scope, a narrative synthesis was undertaken. Mass staff changeover was investigated in 37 studies; the majority (22) of these did not show strong evidence of worse outcomes. Of the 47 studies that examined outcomes across meteorological or calendar seasons, 33 found evidence of seasonal variation. Outcomes were often worse in winter (16 studies). This trend was particularly prominent amongst surgical procedures classed as an 'emergency' (five of nine studies). There was evidence for increased postoperative surgical site infections during summer (seven of 12 studies examining this concept). CONCLUSION: This systematic review provides tentative evidence for an increased risk of postoperative surgical site infections in summer, and an increased risk of worse outcomes after emergency surgery in winter and during staff changeover times. CLINICAL TRIAL REGISTRATION: PROSPERO CRD42019137214.

Cryoablation Without Excision for Low-Risk Early-Stage Breast Cancer: 3-Year Interim Analysis of Ipsilateral Breast Tumor Recurrence in the ICE3 Trial.

BACKGROUND: The ICE3 trial is designed to evaluate the safety and efficacy of breast cryoablation, enabling women older than 60 years with low-risk early-stage breast cancers to benefit from a nonsurgical treatment and to avoid the associated surgical risks. METHODS: The ICE3 trial is a prospective, multi-center, single-arm, non-randomized trial including women age 60 years or older with unifocal, ultrasound-visible invasive ductal carcinoma size 1.5 cm or smaller and classified as low to intermediate grade, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. Ipsilateral breast tumor recurrence (IBTR) at 5 years was the primary outcome. A 3-year interim analysis of IBTR was performed, and the IBTR probability was estimated using the Kaplan-Meier method. RESULTS: Full eligibility for the study was met by 194 patients, who received successful cryoablation per protocol. The mean age was 75 years (range, 55-94 years). The mean tumor length was 8.1 mm (range, 8-14.9 mm), and the mean tumor width was 7.4 mm (range, 2.8-14 mm). During a mean follow-up period of 34.83 months, the IBTR rate was 2.06% (4/194 patients). Device-related adverse events were reported as mild in 18.4% and moderate in 2.4% of the patients. No severe device-related adverse events were reported. More than 95% of the patients and 98% of the physicians reported satisfaction with the cosmetic results at the clinical follow-up evaluation. CONCLUSIONS: Breast cryoablation presents a promising alternative to surgery while offering the benefits of a minimally invasive procedure with minimal risks. Further study within a clinical trial or registry is needed to confirm cryoablation as a viable alternative to surgical excision for appropriately selected low-risk patients.

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

Exploring Male Multiple Orgasm in a Large Online Sample: Refining Our Understanding.

BACKGROUND: The scientific literature on multiple orgasm in males is small. There is little consensus on a definition, and significant controversy about whether multiple orgasm is a unitary experience. AIMS: This study has 2 goals: (i) describing the experience of male multiple orgasm; (ii) investigating whether there are different profiles of multiple orgasm in men. METHODS: Data from a culturally diverse online convenience sample of 122 men reporting multiple orgasm were collected. Data reduction analyses were conducted using principal components analysis (PCA) on 13 variables of interest derived from theory and the existing literature. A K-means cluster analysis followed, from which a 4-cluster solution was retained. RESULTS: While the range of reported orgasms varied from 2 to 30, the majority (79.5%, N = 97) of participants experienced between 2 and 4 orgasms separated by a specific time interval during which further stimulation was required to achieve another orgasm. Most participants reported maintaining their erections throughout and ejaculating with every orgasm. Age was not a significant correlate of the multiple orgasm experience which occurred more frequently in a dyadic context. Four different profiles of multiorgasmic men were described. STRENGTHS & LIMITATIONS: This study constitutes a rare attempt to collect systematic self-report data concerning the experience of multiple orgasm in a relatively large sample. Limitations include the lack of validated measures, memory bias associated with self-reported data and retrospective designs, the lack of a control group and of physiological measurement. CONCLUSION: Our study suggests that multiple orgasm in men is not a unitary phenomenon and sets the stage for future self-report and laboratory study. Griffin-Mathieu G, Berry M, Shtarkshall RA, Amsel R, Binik YM, Gérard M. Exploring Male Multiple Orgasm in a Large Online Sample: Refining Our Understanding. J Sex Med 2021;XX:XXX-XXX.

Rethinking emotional eating: Retrospective and momentary indices of emotional eating represent distinct constructs.

Emotional eating (EE) has been proposed as a key weight loss barrier. However, most investigations of EE rely on retrospective self-reports, which may have poor construct validity. This study evaluated concordance between a common self-report EE measure and a novel method for assessing momentary EE using ecological momentary assessment (EMA). We further assessed the utility of both measures for predicting both BMI and weight outcomes. Participants with overweight or obesity enrolled in a weight loss trial (N = 163) completed a self-report measure of EE and underwent an EMA protocol that assessed momentary emotions and eating behaviors. Momentary EE was derived from EMA data using generalized linear mixed-effects models. Linear regression models examined associations between both EE measures and concurrent BMI as well as weight losses over 30 months. Retrospectively self-reported EE and momentary EE were negatively correlated with one another (r = -0.27). Higher momentary EE and higher retrospectively reported EE both predicted higher concurrent BMI, and higher retrospectively reported EE predicted poorer weight loss outcomes at all time points (p < 0.05). By contrast, higher momentary EE predicted improved weight outcomes at 1-year and 2-year follow-up (p < 0.05). Our findings extend prior research suggesting that retrospective self-report EE measures capture a different construct than intended and suggest that momentary EE could predict improved weight loss outcomes.

The "self" in pain: high levels of schema-enmeshment worsen fibromyalgia impact.

OBJECTIVE: Chronic pain can have detrimental effects on quality of life and a profound impact on one's identity. The Pictorial Representation of Illness- and Self-Measure (PRISM), is a visual tool designed to measure the self-illness separation (SIS) that represents the degree of schema-enmeshment (i.e., the degree to which the self-schema and the illness-schema come to overlap). Our aim was to investigate the relationship between schema-enmeshment and pain-related outcomes in patients with fibromyalgia. METHODS: In this cross-sectional study, 114 patients with fibromyalgia completed self-report assessments of pain catastrophizing, pain severity and interference, impact of symptoms, anxiety, and depression. SIS was assessed using an iPad version of PRISM. Mediation analyses evaluated the mediating role of schema-enmeshment on the association between pain catastrophizing and fibromyalgia impact. RESULTS: A higher degree of schema-enmeshment was associated with greater pain catastrophizing, pain severity and interference, impact of symptoms, and depression. Moreover, a mediation analysis revealed that schema-enmeshment significantly mediated the association between pain catastrophizing and fibromyalgia impact (p < 0.001). CONCLUSIONS: Our results indicate that schema-enmeshment is associated with greater intrusiveness of chronic pain on everyday life, thereby posing significant limitations on the emotional and physical well-being of fibromyalgia patients. Schema-enmeshment also appears to partly account for the deleterious effect of pain catastrophizing on disease impact. The PRISM is a simple tool that may uniquely capture the extent to which chronic pain and illness infiltrates and affects one's self-concept.

Relationship between an editor in chief's commentary publications and the impact factor of cardiovascular medicine journals.

Journal impact factor (IF) inflation is suggested as a problem resulting from commentaries published by the editors in chief (EiCs) of their respective journals. However, it is unclear whether this is a systemic problem across the top thirty cardiovascular medicine journals. Therefore, the purpose of this investigation was to examine the relationship between the number of commentaries written by an EiC and their journal's IF and Eigenfactor (Ef). Utilizing Spearman rank partial correlations controlling for length of service as the EiC, significant moderate correlations were found between the number of commentaries and the number of first-author commentaries by the EiC and the IF of their journal (r=0.568, p=0.001 and r=0.504, p=0.005; respectively). A weak but still significant correlation was found between the number of commentaries by the EiC and the Ef of their journal (r=0.431, p=0.020). The reason for these correlations is unclear, and whether the methodology used to compute the IF and Ef should be modified needs further research.

A randomized pilot study of nitrate supplementation with beetroot juice in acute respiratory failure.

Nitrate rich beetroot juice (BRJ) can enhance nitric oxide signaling, leading to improved physical function in healthy and diseased populations, but its safety and biologic efficacy have not been evaluated in a critically ill population. We randomized 22 previously functional acute respiratory failure patients to either BRJ or placebo daily until day 14 or discharge. We measured blood nitrate and nitrite levels and quantified strength and physical function at intensive care unit (ICU) and hospital discharge. Participants were predominantly male (54%), aged 68.5 years with an APACHE III score of 62. BRJ increased plasma nitrate (mean 219.2 µM increase, p = 0.002) and nitrite levels (mean 0.144 µM increase, p = 0.02). We identified no adverse events. The unadjusted and adjusted effect sizes of the intervention on the short physical performance battery were small (d = 0.12 and d = 0.17, respectively). In this pilot trial, administration of BRJ was feasible and safe, increased blood nitrate and nitrate levels, but had a small effect on physical function. Future studies could evaluate the clinical efficacy of BRJ as a therapy to improve physical function in survivors of critical illness.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.

Brief Self-Compassion Training Alters Neural Responses to Evoked Pain for Chronic Low Back Pain: A Pilot Study.

OBJECTIVE: Self-compassion meditation, which involves compassion toward the self in moments of suffering, shows promise for improving pain-related functioning, but its underlying mechanisms are unknown. This longitudinal, exploratory pilot study investigated the effects of a brief (eight contact hours, two weeks of home practice) self-compassion training on pain-related brain processing in chronic low back pain (cLBP). METHODS: We evaluated functional magnetic resonance imaging (fMRI) response to evoked pressure pain and its anticipation during a self-compassionate state and compared altered brain responses following training with changes on self-reported measures of self-compassion (Self-Compassion Scale [SCS]), interoceptive awareness (Multidimensional Assessment of Interoceptive Awareness [MAIA]), and clinical pain intensity. RESULTS: In a sample of participants with cLBP (N = 20 total, N = 14 with complete longitudinal data) who underwent self-compassion training, we observed reduced clinical pain intensity and disability (P < 0.01) and increased trait self-compassion and interoceptive awareness (all P < 0.05) following training. Evoked pressure pain response in the right temporo-parietal junction (TPJ) was reduced following training, and decreases were associated with reduced clinical pain intensity. Further, increased fMRI responses to pain anticipation were observed in the right dorsolateral prefrontal cortex (dlPFC) and ventral posterior cingulate cortex (vPCC), and these increases were associated with mean post-training changes in SCS scores and scores from the body listening subscale of the MAIA. DISCUSSION: These findings, though exploratory and lacking comparison with a control condition, suggest that self-compassion training supports regulation of pain through the involvement of self-referential (vPCC), salience-processing (TPJ), and emotion regulatory (dlPFC) brain areas. The results also suggest that self-compassion could be an important target in the psychotherapeutic treatment of cLBP, although further studies using controlled experimental designs are needed to determine the specificity of these effects.

The fear and risk of community falls in patients following an intensive care admission: An exploratory cohort study.

BACKGROUND: Muscle weakness and impairments in physical functioning are well-recognised sequelae after critical illness. Whether individuals have a higher risk of community falls and a fear of falling has not been examined amongst individuals after critical illness. OBJECTIVES: The objective of this study was to explore the prevalence of falls, fear of falling, and fall risk in intensive care unit (ICU) survivors over a 6-month period after hospital discharge. METHODS: This was a nested exploratory study within a medical ICU. Fall prevalence was measured in line with established guidelines over 6 months after ICU discharge. Fear of falling and prediction of fall risk were assessed at 2, 4, and 6 months after discharge. RESULTS: Twelve individuals were included. Half of the cohort (n = 6) had at least one fall, with one-third sustaining more than one fall. There were 17 falls reported across the six individuals. Injuries requiring medical intervention were reported with five falls. Almost one-third were classified as 'moderate' to 'severe' injurious falls. Loss of balance and fatigue were reported as the main contributors to the falls. All individuals who had a fall reported a severe fear of falling at 2 months. Individuals classified as having 'moderate' to 'high' risk of falls at 2 months were more likely to have at least one fall. CONCLUSIONS: This study suggests that ICU survivors may have a high fall risk, fear of falling, and fall prevalence, which can result in significant injury.

The structured 'low temperature' phase of the retinal population code.

Recent advances in experimental techniques have allowed the simultaneous recordings of populations of hundreds of neurons, fostering a debate about the nature of the collective structure of population neural activity. Much of this debate has focused on the empirical findings of a phase transition in the parameter space of maximum entropy models describing the measured neural probability distributions, interpreting this phase transition to indicate a critical tuning of the neural code. Here, we instead focus on the possibility that this is a first-order phase transition which provides evidence that the real neural population is in a 'structured', collective state. We show that this collective state is robust to changes in stimulus ensemble and adaptive state. We find that the pattern of pairwise correlations between neurons has a strength that is well within the strongly correlated regime and does not require fine tuning, suggesting that this state is generic for populations of 100+ neurons. We find a clear correspondence between the emergence of a phase transition, and the emergence of attractor-like structure in the inferred energy landscape. A collective state in the neural population, in which neural activity patterns naturally form clusters, provides a consistent interpretation for our results.

Predictive information in a sensory population.

Guiding behavior requires the brain to make predictions about the future values of sensory inputs. Here, we show that efficient predictive computation starts at the earliest stages of the visual system. We compute how much information groups of retinal ganglion cells carry about the future state of their visual inputs and show that nearly every cell in the retina participates in a group of cells for which this predictive information is close to the physical limit set by the statistical structure of the inputs themselves. Groups of cells in the retina carry information about the future state of their own activity, and we show that this information can be compressed further and encoded by downstream predictor neurons that exhibit feature selectivity that would support predictive computations. Efficient representation of predictive information is a candidate principle that can be applied at each stage of neural computation.

Thermodynamics and signatures of criticality in a network of neurons.

The activity of a neural network is defined by patterns of spiking and silence from the individual neurons. Because spikes are (relatively) sparse, patterns of activity with increasing numbers of spikes are less probable, but, with more spikes, the number of possible patterns increases. This tradeoff between probability and numerosity is mathematically equivalent to the relationship between entropy and energy in statistical physics. We construct this relationship for populations of up to N = 160 neurons in a small patch of the vertebrate retina, using a combination of direct and model-based analyses of experiments on the response of this network to naturalistic movies. We see signs of a thermodynamic limit, where the entropy per neuron approaches a smooth function of the energy per neuron as N increases. The form of this function corresponds to the distribution of activity being poised near an unusual kind of critical point. We suggest further tests of criticality, and give a brief discussion of its functional significance.

Comparison of Effects of Endurance and Strength Training Programs in Patients with COPD.

Comparisons between endurance and strength training in chronic obstructive pulmonary disease (COPD) patients have produced equivocal findings when examining physical function and health-related quality of life (HRQL). One reason for these differences may be due to individual patient responses to the different training modalities. PURPOSE: To compare changes in physical function and HRQL in a group of COPD patients completing both an endurance and a strength training program. METHODS: Eleven mildly diseased patients completed a three month endurance training program and, approximately 5 years later, completed a three month strength training program. Changes in 6 minute walk distance (6 MW), time to rise from a chair five times (CRT), and the total score and subscores from the SF-36 and Chronic Respiratory Disease Questionnaire (CRQ) were examined. RESULTS: The forced expiratory volume as a percent of predicted remained relatively constant over the 5 years (61.1 ± 5.9 vs. 60.0 ± 10.3). Endurance and strength training increased 6 MW by 48.2 ± 11.2 (p = 0.008) and 39.8 ± 9.8 (p = 0.001) meters, respectively. Endurance and strength training decreased CRT by 4.8 ± 0.7 (p = 0.001) and 1.3 ± 1.2 (p = 0.056) seconds, respectively. Endurance training resulted in greater improvements in HRQL as compared to strength training. CONCLUSION: These results show that walk distance improves as a result of participating in either an endurance or a strength training program. However, an endurance training program leads to greater improvements in both general and disease specific measures of HRQL.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017.

The NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling for hereditary cancer syndromes and risk management recommendations for patients who are diagnosed with a syndrome. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer. The NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. The NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding risk management for carriers of moderately penetrant genetic mutations associated with breast and/or ovarian cancer.