Polygenic risk in familial breast cancer: Changing the dynamics of communicating genetic risk.

Hereditary breast cancer is associated with known genetic changes: either variants that affect function in a few rare genes or an ever-increasing number of common genomic risk variants, which combine to produce a cumulative effect, known as a polygenic risk (PR) score. While the clinical validity and utility of PR scores are still being determined, the communication of PR is a new challenge for genetic health professionals. This study investigated how PR scores are discussed in the familial cancer clinic compared with a previous study assessing the communication of monogenic risk (MR) for breast cancer. Sixty-five PR consultations between genetic health professionals and women at familial risk of breast cancer were audiotaped, transcribed, and coded using a methodology adapted from the MR study. Analysis of consultations shows that while there were similarities in communicating MR and PR, the complexity and novelty of the polygenic information influenced the style of counseling used by genetic health professionals toward a teaching model of genetic counseling, rather than a patient-centered approach. In particular, compared to MR consultations, in PR consultations significantly fewer counselees (a) were asked about their reasons for attending genetic counseling; or (b) had their information preferences, decision-making style, medical knowledge, understanding, or concerns checked. In conclusion, it is anticipated that PR scores will become part of standard clinical practice. Thus, it will be important for all genetic health professionals to be appropriately educated so that they can tailor their communication to meet patient needs.

Breast cancer polygenic risk scores: a 12-month prospective study of patient reported outcomes and risk management behavior.

PURPOSE: To prospectively assess patient reported outcomes and risk management behavior of women choosing to receive (receivers) or decline (decliners) their breast cancer polygenic risk score (PRS). METHODS: Women either unaffected or affected by breast cancer and from families with no identified pathogenic variant in a breast cancer risk gene were invited to receive their PRS. All participants completed a questionnaire at study enrollment. Receivers completed questionnaires at two weeks and 12 months after receiving their PRS, and decliners a second questionnaire at 12 months post study enrollment. RESULTS: Of the 208 participants, 165 (79%) received their PRS. Among receivers, there were no changes in anxiety or distress following testing. However, compared to women with a low PRS, those with a high PRS reported greater genetic testing-specific distress, perceived risk, decisional regret, and less genetic testing-positive response. At 12 months, breast screening and uptake of risk-reducing strategies were consistent with current Australian guidelines of breast cancer risk management. Reasons for declining PRS included being unable to attend the appointment in person and concerns over potential emotional response. CONCLUSION: The outcomes of the study provide insight into women's responses to receiving PRS and highlight the issues that need to be addressed in the associated model of genetic counseling.

Uptake of polygenic risk information among women at increased risk of breast cancer.

Polygenic risk scores (PRSs) are increasingly being implemented to assess breast cancer risk. This study aimed to assess and determine factors associated with uptake of PRS among women at increased risk of breast cancer for whom genetic testing to date had been uninformative. Participants were recruited from the Variants in Practice study from which breast cancer PRS had been calculated. Four hundred women were notified by letter of the availability of their PRS and invited to complete a self-administered survey comprising several validated scales. Considering non-participants, uptake of PRS was between 61.8% and 42.1%. Multivariate logistic regression identified that women were more likely to receive their PRS if they reported greater benefits (odds ratio [OR] = 1.17, P = .011) and fewer barriers to receiving their PRS (OR = 0.80, P = .007), had completed higher level education (OR = 3.32, P = .004), and did not have daughters (0.29, P = .006). Uptake of breast cancer PRS varied according to several testing- and patient-related factors. Knowledge of these factors will facilitate the implementation of polygenic testing in clinical practice and support informed decision making by patients.

"It wasn't just for me": Motivations and implications of genetic testing for women at a low risk of hereditary breast and ovarian cancer syndrome.

OBJECTIVE: Genetic testing for hereditary breast and ovarian cancer (HBOC) due to pathogenic variants in BRCA1 or BRCA2 is why most women present to familial cancer centers. Despite being assessed as low risk for HBOC, many women proceed with genetic testing. This study explored the genetic testing experiences of unaffected women at low risk of HBOC to clarify what motivates these women to have testing, and what are the implications of the results. METHODS: A qualitative approach was taken. Participants included women who had genetic testing for HBOC from 2016-2018 at the Parkville Familial Cancer Centre in Melbourne, Australia. In-depth, semi-structured interviews were conducted, and thematic analysis was undertaken on transcripts; transcripts were coded, codes were organized into a hierarchical system of categories/subcategories, and key themes were identified. RESULTS: Analysis of 19 transcripts identified five themes: family underpinned all motivators for HBOC genetic testing; health professionals were influential throughout the process; participants were planning for a positive result; results influenced screening-anxiety and frequency; and negative results gave participants relief in many different ways. The three participants with positive results reported feeling shocked at the results and empowered giving this information to family members. CONCLUSIONS: Women at low HBOC risk may be motivated to seek genetic testing, and access to this is increasingly offered through non-genetic health professionals. Professionals can support clients through genetic testing by recognizing familial experiences, providing accurate information, addressing risk perceptions, and understanding cancer anxiety felt by many women.

Family communication following a diagnosis of myotonic dystrophy: To tell or not to tell?

Family communication about genetic information enables informed medical and reproductive decision-making. The literature suggests that a significant proportion of genetically at-risk family members remain uninformed about genetic risk information as a result of non-disclosure. This study explored the experiences of New Zealand families communicating about a diagnosis of type 1 myotonic dystrophy (DM1). Eligible individuals were identified and recruited from the New Zealand (NZ) MD Prev study, a nationwide study which aimed to determine the prevalence, impact, and costs of genetic muscle disorders across the lifespan. Twelve qualitative semi-structured interviews were conducted with 17 participants. The findings demonstrate diversity among and within families, with several distinct family narratives described. Most participants reported a motivation to tell relatives about their diagnosis to promote autonomy. Women were pivotal throughout communication processes and this was often tied to the concept of maternal responsibility and a desire to promote relatives' reproductive autonomy. The diagnosis of DM1 and the subsequent family communication decisions altered relationships for many, with both positive and negative impacts described. The findings demonstrate that individuals require time to explore the impact of a diagnosis of DM1 on self, family and intimate partner relationships to anticipate unique communication challenges. Genetic counselors can use these findings to inform their approach to counseling families with DM1. Longitudinal genetic counseling may be beneficial as a way to provide individuals with life stage specific support as they communicate with their relatives about a diagnosis of DM1.

Socio-Structural Factors and HIV Care Engagement among People Living with HIV during the COVID-19 Pandemic: A Qualitative Study in the United States.

Achieving HIV prevention goals will require successful engagement in each stage of the HIV continuum. The present study sought to understand the ways in which socio-structural factors influence HIV care engagement among people living with HIV (PLH) within the context of the ongoing COVID-19 pandemic. Twenty-five PLH were recruited from January to October 2021. Semi-structured interviews discussed various socio-contextual factors that influenced engagement in HIV-related care as a result of the pandemic. A thematic content analysis reported semantic level themes describing factors influencing HIV care following an integrated inductive-deductive approach. Qualitative analysis revealed three themes that either supported or hindered engagement in care within the context of the COVID-19 pandemic: (1) social determinants of health, (2) social support, and (3) modes of healthcare delivery. The results underscore the need to assess socio-structural factors of health as means to promote successful engagement in the HIV care continuum and shed new insights to guide future practice in the era of COVID-19.

Case Report: Hypoglycemia Due to a Novel Activating Glucokinase Variant in an Adult - a Molecular Approach.

We present a case of an obese 22-year-old man with activating GCK variant who had neonatal hypoglycemia, re-emerging with hypoglycemia later in life. We investigated him for asymptomatic hypoglycemia with a family history of hypoglycemia. Genetic testing yielded a novel GCK missense class 3 variant that was subsequently found in his mother, sister and nephew and reclassified as a class 4 likely pathogenic variant. Glucokinase enables phosphorylation of glucose, the rate-limiting step of glycolysis in the liver and pancreatic ß cells. It plays a crucial role in the regulation of insulin secretion. Inactivating variants in GCK cause hyperglycemia and activating variants cause hypoglycemia. Spleen-preserving distal pancreatectomy revealed diffuse hyperplastic islets, nuclear pleomorphism and periductular islets. Glucose stimulated insulin secretion revealed increased insulin secretion in response to glucose. Cytoplasmic calcium, which triggers exocytosis of insulin-containing granules, revealed normal basal but increased glucose-stimulated level. Unbiased gene expression analysis using 10X single cell sequencing revealed upregulated INS and CKB genes and downregulated DLK1 and NPY genes in ß-cells. Further studies are required to see if alteration in expression of these genes plays a role in the metabolic and histological phenotype associated with glucokinase pathogenic variant. There were more large islets in the patient's pancreas than in control subjects but there was no difference in the proportion of ß cells in the islets. His hypoglycemia was persistent after pancreatectomy, was refractory to diazoxide and improved with pasireotide. This case highlights the variable phenotype of GCK mutations. In-depth molecular analyses in the islets have revealed possible mechanisms for hyperplastic islets and insulin hypersecretion.

Communicating polygenic risk scores in the familial breast cancer clinic.

OBJECTIVE: To describe the communication of polygenic risk scores (PRS) in the familial breast cancer setting. METHODS: Consultations between genetic healthcare providers (GHP) and female patients who received their PRS for breast cancer risk were recorded (n = 65). GHPs included genetic counselors (n = 8) and medical practitioners (n = 5) (i.e. clinical geneticists and oncologists). A content analysis was conducted and logistic regression was used to assess differences in communication behaviors between genetic counselors (n = 8) and medical practitioners (n = 5). RESULTS: Of the 65 patients, 31 (47.7 %) had a personal history of breast cancer, 18 of whom received an increased PRS (relative risk >1.2). 25/34 unaffected patients received an increased PRS. Consultations were primarily clinician-driven and focused on biomedical information. There was little difference between the biomedical information provided by genetic counselors and medical practitioners. However, genetic counselors were significantly more likely to utilize strategies to build patient rapport and counseling techniques. CONCLUSIONS: Our findings provide one of the earliest reports on how breast cancer PRSs are communicated to women. PRACTICE IMPLICATIONS: Key messages for communicating PRSs were identified, namely: discussing differences between polygenic and monogenic testing, the multifactorial nature of breast cancer risk, polygenic inheritance and current limitation of PRSs.

Impact of direct-to-consumer genetic testing on Australian clinical genetics services.

The increasing popularity of direct-to-consumer genetic testing (DTCGT) is thought to be creating a burden on clinical genetic services worldwide. However, no Australian studies have collected recent evidence regarding this impact. We surveyed Australian clinical genetics services about DTCGT-related referrals over the past 10 years. Eleven publicly-funded services reported over 100 DTCGT-related referrals. Most (83%) involved general practitioners seeking interpretation of DTCGT results. More than 30% involved imputed risk estimates from third-party software tools. Services reported low validation rates for DTCGT results (<10%), and variable procedures for managing DTCGT referrals, with most (8/11) lacking specific procedures. Our study helps quantify the impact of DTCGT on clinical genetics services, and highlights the impact of imputed risk estimates.

Carbon nanotubes for immunomagnetic separation of Escherichia coli O157: H7.

Bovine serum albumin-functionalized multiple-walled carbon nanotubes with encapsulated ferromagnetic elements were conjugated with pathogen-specific antibody, and the conjugate was evaluated for immunomagnetic separation of Escherichia coli O157:H7 in pure and mixed (with Salmonella Typhimurium) cultures.

Visualizing adhesion-induced agglutination of Escherichia coli with mannosylated nanoparticles.

Polymeric nanoparticles covalently functionalized with derivatized D-mannose molecules were synthesized and characterized. These nanoparticles have an average size of approximately 160 nm in diameter, thus bearing a large number of surface-tethered mannose moieties for multivalent interactions with adhesins on bacterial cells. Specifically, the mannosylated nanoparticles bind strongly with Escherichia coli, allowing the convenient visualization of adhesion interactions under a conventional electron microscope. Since a single nanoparticle is capable of binding more than one cell, the adhesion interactions result in significant nanoparticle-mediated cell agglutination according to electron microscopy imaging. Potential applications of the mannosylated nanoparticles in the inhibition of enteropathogenic infections are discussed.

RESS for the preparation of fluorinated porphyrin nanoparticles.

Rapid Expansion of Supercritical Solutions (RESS) was used to produce clean, surfactant-free nanoparticles (average size = 60 nm) of a fluorinated tetraphenylporphyrin from supercritical solutions with CO2.

Age differences in visits to office-based physicians by patients with diabetes: United States, 2010.

KEY FINDINGS: Data from the National Ambulatory Medical Care Survey. Office-based physician visits by patients with diabetes increased 20%, from 94.4 million in 2005 to 113.3 million in 2010, but the rate did not change between 2005 and 2010. The visit rate for diabetes increased with age and averaged 1,380 visits per 1,000 persons aged 65 and over in 2010. A majority of visits made by patients with diabetes (87%) were by those with multiple chronic conditions, and the number of chronic conditions increased with advancing age. Medications were prescribed or continued at a majority of visits (85%) made by patients with diabetes, with the number of medications prescribed or continued increasing as age increased. Diabetes is a chronic condition which affects nearly 29 million Americans and is a major cause of other chronic conditions, including heart disease, eye disease, and stroke (1). Diabetes was the seventh leading U.S. cause of death in 2009 and 2010 (2,3). Management of diabetes costs nearly $245 billion annually, and patients with diabetes have medical expenditures approximately 2.3 times higher than those for patients without diabetes (4). This data brief shows the trend from 2005 through 2010 for visits to office-based physicians by patients with diabetes, and describes age differences in the utilization of health care by patients with diabetes in 2010.