Mainstream Germline Genetic Testing with Expanded Eligibility for Early Breast Cancer Patients in a Large Integrated Health System.

BACKGROUND: This study evaluated a new mainstream genetic testing pathway for hereditary cancer, with expanded eligibility for early-stage breast cancer patients. METHODS: The study compared multigene panel (62 genes) germline testing uptake and results for breast cancer patients at 4 pilot sites (n = 502 patients) and 10 non-pilot sites (n = 1792 patients) within Kaiser Permanente Northern California from December 2020, to June 2021. At the pilot sites, breast care coordinators (BCCs) offered and consented patients for testing, with eligibility expanded to include all patients age 65 years or younger. At the non-pilot sites, eligible patients were referred to genetics for pre-test counseling, ordering, and follow-up evaluation with the standard guideline that included all patients age 45 years or younger. RESULTS: Demographic and disease characteristics were similar at the pilot and non-pilot sites. At the pilot verses non-pilot sites, a higher percentage of patients was tested overall (61.6% vs 31.7%) and across all age groups. The median time from breast biopsy to test result also was reduced (22 vs 33 days, respectively). A higher percentage of patients at the pilot sites was identified as having a pathogenic/likely pathogenic variant (PV/LPV) in a breast cancer-related gene (3.6% vs 1.6%). Although the percentage of total patients tested was nearly twofold higher at the pilot sites than at the non-pilot sites, the percentage of total patients seen by genetics was estimated to be similar (33.7% vs 31.7%). CONCLUSION: Mainstream genetic testing of breast cancer patients facilitated by BCCs makes it feasible for a large health care system to expand germline genetic testing to early breast cancer patients age 65 years or younger.

Evaluation of approaches to recruitment of racially and ethnically diverse breast cancer patients from an integrated health care setting for collection of observational social network data.

PURPOSE: We compared approaches to recruitment of diverse women with breast cancer in a study designed to collect complex social network data. METHODS: We recruited 440 women from the Kaiser Permanente Northern California population newly diagnosed with breast cancer, either in person at a clinic, by email, or by mailed letter. In clinic and mail recruitment, women completed a brief 3-page paper survey (epidemiologic data only), and women had the option to complete a separate, longer (30-40 min) personal social network survey online. In email recruitment, we administered epidemiologic and personal social network measures together in a single online survey. In email and mail recruitment, we limited the sample of non-Hispanic white (NHW) women to 30% of their total. We used descriptive analysis and multinomial logistic regression to examine odds of recruitment vs. mailed letter. RESULTS: Women responded to the social network surveys on average 3.7 months post-diagnosis. Mean age was 59.3 (median = 61.0). In-person clinic recruitment was superior with a 52.1% success rate of recruitment compared with 35.6% by mail or 17.3% by email (χ2 = 65.9, p < 0.001). Email recruitment produced the highest completion rate (82.1%) of personal network data compared with clinic (36.5%) or mail (28.7%), (χ2 = 114.6, p < 0.001). Despite intentional undersampling of NHW patients, response rates for Asian, Hispanic, and Black women by email were lower. However, we found no significant differences in recruitment rates by race and ethnicity for face-to-face clinic recruitment vs. by letter. Letter recruitment produced the highest overall response. CONCLUSION: Mailed letter was the best approach to representative recruitment of diverse women with breast cancer and collection of social network data, and further yielded the highest absolute response.

Influenza Vaccine Effectiveness by A(H3N2) Phylogenetic Subcluster and Prior Vaccination History: 2016-2017 and 2017-2018 Epidemics in Canada.

BACKGROUND: The influenza A(H3N2) vaccine was updated from clade 3C.3a in 2015-2016 to 3C.2a for 2016-2017 and 2017-2018. Circulating 3C.2a viruses showed considerable hemagglutinin glycoprotein diversification and the egg-adapted vaccine also bore mutations. METHODS: Vaccine effectiveness (VE) in 2016-2017 and 2017-2018 was assessed by test-negative design, explored by A(H3N2) phylogenetic subcluster and prior season's vaccination history. RESULTS: In 2016-2017, A(H3N2) VE was 36% (95% confidence interval [CI], 18%-50%), comparable with (43%; 95% CI, 24%-58%) or without (33%; 95% CI, -21% to 62%) prior season's vaccination. In 2017-2018, VE was 14% (95% CI, -8% to 31%), lower with (9%; 95% CI, -18% to 30%) versus without (45%; 95% CI, -7% to 71%) prior season's vaccination. In 2016-2017, VE against predominant clade 3C.2a1 viruses was 33% (95% CI, 11%-50%): 18% (95% CI, -40% to 52%) for 3C.2a1a defined by a pivotal T135K loss of glycosylation; 60% (95% CI, 19%-81%) for 3C.2a1b (without T135K); and 31% (95% CI, 2%-51%) for other 3C.2a1 variants (with/without T135K). VE against 3C.2a2 viruses was 45% (95% CI, 2%-70%) in 2016-2017 but 15% (95% CI, -7% to 33%) in 2017-2018 when 3C.2a2 predominated. VE against 3C.2a1b in 2017-2018 was 37% (95% CI, -57% to 75%), lower at 12% (95% CI, -129% to 67%) for a new 3C.2a1b subcluster (n = 28) also bearing T135K. CONCLUSIONS: Exploring VE by phylogenetic subcluster and prior vaccination history reveals informative heterogeneity. Pivotal mutations affecting glycosylation sites, and repeat vaccination using unchanged antigen, may reduce VE.

Improving Weight Measurement Compliance in the Intensive Care Unit.

Fluid management is crucial in patients with end stage kidney disease, and weight measurement is an integral component of safe and effective care. Weight trends can indicate changes in volume status, especially in the acute care settings, but they are often missed. The purpose of this quality improvement project was to increase bodyweight measurement compliance rates in patients admitted to the intensive care unit by creating an automatic order generating a task list reminder on the nursing staff worklist. One month of data was collected pre-intervention and one month post intervention. Results indicate an increase in the percentage of weights taken post-intervention (p = 62.1%, SD = 11.2; p = 0.001) compared to pre-intervention (p = 28.9%, SD = 9.8).

Vaccine Effectiveness Against Lineage-matched and -mismatched Influenza B Viruses Across 8 Seasons in Canada, 2010-2011 to 2017-2018.

Vaccine effectiveness (VE) against influenza B was derived separately for Victoria and Yamagata lineages across 8 seasons (2010-2011 to 2017-2018) in Canada when trivalent influenza vaccine was predominantly used. VE was ≥50% regardless of lineage match to circulating viruses, except when the vaccine strain was unchanged from the prior season.

Evaluation of a validated methylation triage signature for human papillomavirus positive women in the HPV FOCAL cervical cancer screening trial.

Human papillomavirus (HPV)-based cervical cancer screening requires triage of HPV positive women to identify those at risk of cervical intraepithelial neoplasia grade 2 (CIN2) or worse. We conducted a blinded case-control study within the HPV FOCAL randomized cervical cancer screening trial of women aged 25-65 to examine whether baseline methylation testing using the S5 classifier provided triage performance similar to an algorithm relying on cytology and HPV genotyping. Groups were randomly selected from women with known HPV/cytology results and pathology outcomes. Group 1: 104 HPV positive (HPV+), abnormal cytology (54 CIN2/3; 50

Interim estimates of 2018/19 vaccine effectiveness against influenza A(H1N1)pdm09, Canada, January 2019.

Using a test-negative design, the Canadian Sentinel Practitioner Surveillance Network assessed interim 2018/19 vaccine effectiveness (VE) against predominant influenza A(H1N1)pdm09 viruses. Adjusted VE was 72% (95% confidence interval: 60 to 81) against medically attended, laboratory-confirmed influenza A(H1N1)pdm09 illness. This substantial vaccine protection was observed in all age groups, notably young children who appeared to be disproportionately affected. Sequence analysis identified heterogeneity in emerging clade 6B.1 viruses but no dominant drift variant.

The Influence of Presentation Format of Story on Narrative Production in Chinese Children Learning English-as-a-Second-Language: A Comparison Between Graphic Novel, Illustration Book and Text.

Past studies have shown that multimodal presentation of story can improve story-retelling performance in the first language. The purpose of the present study was to investigate whether similar multimedia effects can be observed in second language learning and graphic novel reading. A total of 51 Chinese elementary school children, aged 7-8, who were learning English as a second language were recruited. They were randomly assigned to one of the three experimental conditions that differed in the format of story presentation: English text, English text with pictorial illustrations or graphic novel. After reading the same story, the children retold the story in English. The narratives produced were then rated by two independent raters. The results of group comparison showed that children from the three experimental groups had similar performance, indicating that multimedia presentation may not always facilitate narrative production in English as a second language. Within-subject comparison further showed that the children were relatively strong in language skills and capturing the main ideas of the story, while showing weakness in story structure awareness, elaboration, as well as local and global cohesion. Suggestions for the application of multimodal presentation of narrative texts are discussed.

Early season co-circulation of influenza A(H3N2) and B(Yamagata): interim estimates of 2017/18 vaccine effectiveness, Canada, January 2018.

Using a test-negative design, we assessed interim vaccine effectiveness (VE) for the 2017/18 epidemic of co-circulating influenza A(H3N2) and B(Yamagata) viruses. Adjusted VE for influenza A(H3N2), driven by a predominant subgroup of clade 3C.2a viruses with T131K + R142K + R261Q substitutions, was low at 17% (95% confidence interval (CI): -14 to 40). Adjusted VE for influenza B was higher at 55% (95% CI: 38 to 68) despite prominent use of trivalent vaccine containing lineage-mismatched influenza B(Victoria) antigen, suggesting cross-lineage protection.

A home-school-doctor model to break the barriers for uptake of human papillomavirus vaccine.

BACKGROUND: A high coverage of human papillomavirus (HPV) vaccination is required to achieve a clinically significant reduction in disease burden. Countries implementing free-of-charge national vaccination program for adolescent girls are still challenged by the sub-optimal uptake rate. Voluntary on-site school-based mass vaccination programs have demonstrated high coverage. Here, we tested whether this could be an option for countries without a government-supported vaccination program as in Hong Kong. METHOD: A Home-School-Doctor model was evolved based on extensive literature review of various health promotion models together with studies on HPV vaccination among adolescent girls. The outcome measure was uptake of vaccination. Factors associated with the outcome were measured by validated surveys in which 4,631 students from 24 school territory wide participated. Chi-square test was used to analyze association between the categorical variables and the outcome. Multivariate analysis was performed to identify independent variables associated with the outcome with vaccine group as case and non-vaccine group as control. RESULTS: In multivariate analysis, parental perception of usefulness of the Home-School-Doctor model had a very high odds ratio for uptake of HPV vaccination (OR 26.6, 95% CI 16.4, 41.9). Paying a reasonable price was another independent factor associated with increased uptake (OR 1.71, 95% CI 1.39, 2.1 for those with parents willing to pay US$125-250 for vaccination). For parents and adolescents who were not sure where to get vaccination, this model was significantly associated with improved uptake rate (OR 1.66, 95% CI 1.23, 2.23). Concerns with side effects of vaccine (OR 0.70, 95% CI 0.55, 0.88), allowing daughters to make their own decisions (OR 0.49, 95% CI 0.38, 0.64) and not caring much about daughters' social life (95% CI 0.45, 0.92) were factors associated with a lower uptake. DISCUSSION: The findings of this study have added knowledge on how a school-based vaccination program would improve vaccine uptake rate even when the users need to pay. Our findings are consistent with other study that the most acceptable way to achieve high uptake of HPV vaccine is to offer voluntary school-based vaccination. CONCLUSION: A model of care incorporating the efforts and expertise of academics and health professionals working closely with school can be applied to improve the uptake of vaccine among adolescent girls. Subsidized voluntary school-based vaccination scheme can be an option.

Immuno-epidemiologic correlates of pandemic H1N1 surveillance observations: higher antibody and lower cell-mediated immune responses with advanced age.

BACKGROUND: Pandemic H1N1 (pH1N1) surveillance data showed lower attack rates but higher risk of severe outcomes with advanced age. We explored immuno-epidemiologic correlates of surveillance findings including humoral and cell-mediated immunity (CMI). METHODS: In an age-based design, ∼100 banked/residual sera per 10-year age stratum were assessed by hemagglutination inhibition (HI) and microneutralization (MN) assays for preexisting antibody to pH1N1 and recent seasonal H1N1 and H3N2 strains. In a separate birth cohort design defined by childhood influenza A/subtype priming (1919-1929: H1N1; 1945-1949: H1N1; 1958-1960: H2N2; 1969-1970: H3N2; 1978-1989: H3N2/H1N1), whole blood was collected from up to 50 volunteers per birth cohort. The ratio of Th1(IFN-γ):Th2(IL-10) cytokine responses was evaluated in vitro. RESULTS: Antibody to seasonal viruses was highest in school-age children. Cross-reactive HI/MN antibody to pH1N1 was low among participants <70 years of age (yoa; 6%/4% ≥ 40), but seroprevalence increased at 70-79 yoa (27%/6%), increased even more at 80-89 yoa (65%/47%), and was highest at ≥90 yoa (88%/76%). CMI to pH1N1 was evident in all 5 birth cohorts but was lower compared with seasonal strains. There was little differentiation by subtype priming, but the Th1:Th2 ratio for all viruses dropped significantly in the 2 oldest cohorts. CONCLUSIONS: Preexisting antibody may have protected the very old from pH1N1 infection, while diminished CMI may have contributed to greater severity once infected. In the young, cross-reactive pH1N1 antibody was mostly absent, while more intact CMI may have protected against severe outcomes.

Delay in funding of tolvaptan for polycystic kidney disease in Aotearoa New Zealand.

Autosomal dominant polycystic kidney disease (ADPKD) is the fifth most common cause of end stage kidney disease (ESKD) in Aotearoa New Zealand. Identification of two genes, PCKD1 and PCKD2, which cause the majority of this disease, has played a key role in the development of DNA-sequence molecular diagnostics. ADPKD is characterised by the formation and growth of multiple cysts within the kidney, with some but not all patients progressing to ESKD. The diagnosis of ADPKD is based on the presence of family history, and radiological imaging although increasingly genetic testing is being used for screening and diagnosis. Once diagnosed, standard management of ADPKD includes laboratory monitoring of chronic kidney disease (CKD) parameters, lowering of blood pressure, and a high fluid intake. Over the last decade much research has been undertaken for targeted therapies for ADPKD; however, despite funding of these medications overseas since May 2015, and applications to Te Pataka Whaioranga, The Pharmaceutical Management Agency (PHARMAC), these therapies remain unavailable to New Zealanders resulting in an increased burden of disease to individuals and the whanau and financial cost to the health system.

The de-guanidinylated derivative of peramivir remains a potent inhibitor of influenza neuraminidase.

The guanidine function in the potent neuraminidase inhibitor peramivir was included early on in the drug design process, and examination of X-ray structural data for the enzyme-inhibitor complex would seem to indicate that the guanidine plays a critical role in promoting binding. However, this functional group may also contribute to the poor oral availability of the drug. Given that the relative stereochemistry on the guanidine-bearing carbon in peramivir is opposite to that in zanamivir (a related neuraminidase inhibitor, for which the guanidine function is known to contribute substantially to the potency), we sought to determine the importance of the guanidine group to peramivir's overall potency. Here we report that the de-guanidinylated analogue of peramivir is only ca. 1-order of magnitude less potent than peramivir itself in two in vitro inhibition assays. This suggests that next-generation inhibitors designed to improve on peramivir's properties might profitably dispense with the guanidine function.

Seasonal influenza vaccine and increased risk of pandemic A/H1N1­related illness: first detection of the association in British Columbia, Canada.

BACKGROUND: In April 2009, an elementary school outbreak of pandemic H1N1 (pH1N1) influenza was reported in a community in northern British Columbia, Canada--an area that includes both non-Aboriginal and Aboriginal residents living on or off a reserve. During the outbreak investigation, we explored the relationship between prior receipt of trivalent inactivated influenza vaccine (TIV) and pH1N1-related illness. METHODS: A telephone survey was conducted from 15 May through 5 June 2009 among households of children attending any school in the affected community. Members of participating households where influenza-like illness (ILI) was described were then invited to submit blood samples for confirmation of pH1N1 infection by hemagglutination inhibition and microneutralization assays. Circulation of pH1N1 was concentrated among households of the elementary school and elsewhere-reserve to which analyses of TIV effect were thus restricted. Odds ratios (ORs) for the TIV effect on ILI were computed through logistic regression, with adjustment for age, comorbidity, household density, and Aboriginal status. The influence of within-household clustering was assessed through generalized-linear-mixed models. RESULTS: Of 408 participants, 92 (23%) met ILI criteria: 29 (32%) of 92 persons with ILI, compared with 61 (19%) 316 persons without ILI, had received the 2008-2009 formulation of TIV. Fully adjusted ORs for 2008-2009 TIV effect on ILI were 2.45 (95% confidence interval, 1.34-4.48) by logistic regression and 2.68 [95% confidence interval, 1.37-5.25) by generalized-linear-mixed model. CONCLUSIONS: An outbreak investigation in British Columbia during the late spring of 2009 provided the first indication of an unexpected association between receipt of TIV and pH1N1 illness. This led to 5 additional studies through the summer 2009 in Canada, each of which corroborated these initial findings.

Prevalence of seroprotection against the pandemic (H1N1) virus after the 2009 pandemic.

BACKGROUND: Before pandemic (H1N1) 2009, less than 10% of serum samples collected from all age groups in the Lower Mainland of British Columbia, Canada, showed seroprotection against the pandemic (H1N1) 2009 virus, except those from very elderly people. We reassessed this profile of seroprotection by age in the same region six months after the fall 2009 pandemic and vaccination campaign. METHODS: We evaluated 100 anonymized serum samples per 10-year age group based on convenience sampling. We measured levels of antibody against the pandemic virus by hemagglutination inhibition and microneutralization assays. We assessed geometric mean titres and the proportion of people with seroprotective antibody levels (hemagglutination inhibition titre ≥ 40). We performed sensitivity analyses to evaluate titre thresholds of 80, 20 and 10. RESULTS: Serum samples from 1127 people aged 9 months to 101 years were obtained. The overall age-standardized proportion of people with seroprotective antibody levels was 46%. A U-shaped age distribution was identified regardless of assay or titre threshold applied. Among those less than 20 years old and those 80 years and older, the prevalence of seroprotection was comparably high at about 70%. Seroprotection was 44% among those aged 20-49 and 30% among those 50-79 years. It was lowest among people aged 70-79 years (21%) and highest among those 90 years and older (88%). INTERPRETATION: We measured much higher levels of seroprotection after the 2009 pandemic compared than before the pandemic, with a U-shaped age distribution now evident. These findings, particularly the low levels of seroprotection among people aged 50-79 years, should be confirmed in other settings and closer to the influenza season.

Influenza Classification Suite: An automated Galaxy workflow for rapid influenza sequence analysis.

Influenza viruses continually evolve to evade population immunity, and the different lineages are assigned into clades based on shared mutations. We have developed a publicly available computational workflow, the Influenza Classification Suite, for rapid clade mapping of sequenced influenza viruses. This suite provides a user-friendly workflow implemented in Galaxy to automate clade calling and antigenic site extraction. Workflow input includes clade definition and amino acid index array files, which can be customized to identify any clades of interest. The Influenza Classification Suite provides rapid, high-resolution understanding of circulating influenza strain evolution to inform influenza vaccine effectiveness and the need for potential vaccine reformulation.

An Aptamer-based Sensor for Unchelated Gadolinium(III).

A method for determining the presence of unchelated trivalent gadolinium ion (Gd3+) in aqueous solution is demonstrated. Gd3+ is often present in samples of gadolinium-based contrast agents as a result of incomplete reactions between the ligand and the ion, or as a dissociation product. Since the ion is toxic, its detection is of critical importance. Herein, the design and usage of an aptamer-based sensor (Gd-sensor) for Gd3+ are described. The sensor produces a fluorescence change in response to increasing concentrations of the ion, and has a limit of detection in the nanomolar range (~100 nM with a signal-to-noise ratio of 3). The assay may be run in an aqueous buffer at ambient pH (~7 - 7.4) in a 384-well microplate. The sensor is relatively unreactive toward other physiologically relevant metal ions such as sodium, potassium, and calcium ions, although it is not specific for Gd3+ over other trivalent lanthanides such as europium(III) and terbium(III). Nevertheless, the lanthanides are not commonly found in contrast agents or the biological systems, and the sensor may therefore be used to selectively determine unchelated Gd3+ in aqueous conditions.

Angiosuppressive properties of marine-derived compounds-a mini review.

Angiogenesis, formation of new blood vessels from preexisting one, is a critical step of tumorgenesis of solid tumors. Therefore, antiangiogenic therapy is one of the promising approaches to control tumor growth. In the past 20 years, a lot of compounds have been tested for their antiangiogenic properties. Bevacizumab, Avastin®, the first antiangiogenic drug approved by the US FDA, has been widely used in clinic for treating cancer. Indeed, many synthetic compounds are highly toxic and exert side effects even though they are effective in inhibiting neovessel formation and cancer cell growth. Using natural compounds or their derivatives is one of the ways to solve these problems. Sinomenine and ginsenosides are common antiangiogenic and anticancer compounds that are extracted from herbal medicines. Recent findings suggested that marine algae-derived natural pigments also possess similar activities. It has been reported that fucoxanthin from Undaria pinnatifida, Siphonaxanthin from Codium fragile, can inhibit angiogenesis and cancer growth effectively. In conclusion, natural compounds derived from marine algae could provide a novel and safe source for new drug development in anticancer and antiangiogenic properties in the future.

Complete Genome Sequence of Mycobacterium chimaera SJ42, a Nonoutbreak Strain from an Immunocompromised Patient with Pulmonary Disease.

Mycobacterium chimaera, a nontuberculous mycobacterium (NTM) belonging to the Mycobacterium avium complex (MAC), is an opportunistic pathogen that can cause respiratory and disseminated disease. We report the complete genome sequence of a strain, SJ42, isolated from an immunocompromised male presenting with MAC pneumonia, assembled from Illumina and Oxford Nanopore data.