Utility of a mainstreamed genetic testing pathway in breast and ovarian cancer patients during the COVID-19 pandemic.

INTRODUCTION: Mainstreamed genetic testing (MGT) obviates the need for a cancer genetics consultation, since trained oncologists (O) and gynaecologists (G) provide counseling, prescribe testing and deliver results. We report results from our MGT program and emphasize its utility during the COVID-19 lockdown, when cancer genetics clinics had suspended their activity. METHODS: An MGT pathway for breast and ovarian cancer (BC/OC) patients was established in Jan-2018 between the Assistance Publique - Hôpitaux de Paris.Sorbonne Université Cancer Genetics team and the Oncology/Gynecology departments at one teaching and two regional hospitals. Trained O + G evaluated patients with the Manchester Scoring System. A 12-point threshold was recommended for testing. Next-generation sequencing of BRCA1, BRCA2, PALB2, RAD51C and RAD51D was performed. Results were delivered to the patient by O/G. Pathogenic variants (PV) carriers were referred to the genetics clinic. Results are reported for the 2nd-Jan-2018 to 1st-June-2020 period. That includes the eight-week COVID-19 lockdown and three-week de-confinement phase 1. RESULTS: Results were available for 231/234 patients. Twenty-eight (12.1%) carried a PV. Of the 27 patients tested during the COVID-19 period, three carried a PV, two in BRCA1 and one in RAD51C. The clinical impact was immediate for the two BRCA1 BC cases undergoing neo-adjuvant chemotherapy, since double mastectomy and salpingo-oophorectomy will now be performed using two-step strategies. CONCLUSIONS: MGT guaranteed care continuity in BC/OC patients during the critical phases of the COVID-19 pandemic, with immediate implications for PV carriers. More broadly, we report for the first time the successful implementation of MGT in France.

Outcomes for women without conventional treatment for stage 1A (microinvasive) carcinoma of the cervix.

BACKGROUND: An unethical clinical study that entailed withholding treatment from women diagnosed with cervical intraepithelial neoplasia 3 (CIN3) was conducted at National Women's Hospital, Auckland, New Zealand. Women with microinvasive carcinoma of the cervix also had treatment withheld. AIMS: To describe the management and outcomes for women with microinvasive carcinoma for many of whom conventional treatment was withheld. MATERIALS AND METHODS: Retrospective cohort study of women with a diagnosis of stage 1A cervical carcinoma at National Women's Hospital. Medical records, cytology and histopathology were reviewed and data linked with cancer and death registries up to December 2000. RESULTS: Between 1955 and 1976, 62 women were initially diagnosed with stage 1A cervical cancer and 20 were diagnosed during follow up (to 1995). Sixty of the 82 women had initial management characterised as 'probably non-curative'; 20 of these received only a small diagnostic excision. Women in the latter group were more likely to: (i) subsequently have positive cytology (P < 0.0005), (ii) have untreated positive cytology (P = 0.02), and (iii) undergo multiple biopsies after initial management (P = 0.001). Of the women who received only a small diagnostic excision, eight of 20 developed invasive carcinoma of the cervix (≥ stage 1B) or vaginal vault, compared to two of 22 women who received initial treatment characterised as 'probably curative'. CONCLUSIONS: Women with microinvasive carcinoma were included in a natural history study of CIN3; they underwent numerous procedures designed to observe rather than treat their condition, and had a substantial risk of invasive cancer.

Comparison of ethical issues in Indian and New Zealand prospective studies of cervical pre-cancer.

The aim was to compare the ethics of historical Indian and New Zealand prospective studies of cervical pre-cancer in terms of: scientific justification, potential harms and benefits to subjects, informed consent procedures, monitoring and stopping, and exploitation. The New Zealand study had poorer scientific justification, greater harm to subjects, absence of informed consent, and greater exploitation. Reasons proposed for on-going criticism of the Indian study are: semantic confusion, lack of consistent detail about informed consent procedures, and failure of a professional obligation to provide on-going medical care. Such criticisms might have been set on a firmer basis, or rejected, if there had been a public judicial inquiry, as happened in New Zealand. Current disagreement about the ethics of randomised trials of cervical screening in India might be resolved through a public inquiry.

Life-Course Relationship between Socioeconomic Circumstances and Timing of First Birth in a Birth Cohort.

OBJECTIVES: This study examines the influence of socioeconomic circumstances in childhood (childhood SES) and adulthood (adult SES) on timing of first birth by age 37. METHODS: A longitudinal study of a 1972-1973 New Zealand birth cohort collected information on socioeconomic characteristics from age 3-32 and reproductive histories at 21, 26, 32 and 38; information on first birth was available from 978 of the original 1037. Relative Risks (RR) and 95% Confidence Intervals (CI) were calculated using Poisson regression to examine first live birth prior to age 21, from 21-25, from 26-31, and from 32-37, by socioeconomic characteristics at different ages. RESULTS: Overall, 68.5% of men had fathered a child and 75.9% of women had given birth, by age 37; with overall differences in parenthood to age 31 for men, and 37 for women evident by childhood SES. While parenthood by age 20 was strongly associated with lower childhood SES for both sexes, first entry into motherhood from 32-37 was more likely with higher adult SES at age 32 (RR = 1.8, 95% CI 1.1-3.0 for medium and RR = 1.9, 95% CI 1.1-3.3 for high compared with low). Education also differientated age at parenthood, with those with higher education more likely to defer fatherhood past age 31, and motherhood past age 25 followed by a period of increased likelihood of motherhood for women with higher levels of education from age 32-37 (RR = 1.4, 95% CI 0.87-2.2 and RR = 1.7, 95% CI 1.1-2.6 for medium and high respectively compared with low). CONCLUSIONS: SES varies across the lifecourse, and SES at the time has the strongest association with first births at that time. Low childhood SES drives adolescent parenthood, with resulting cumulative differences in parenthood past age 30. Those with more education and higher adult SES are deferring parenthood but attempt to catch up in the mid to late thirties.

Prevalence of KISS1 Receptor mutations in a series of 603 patients with normosmic congenital hypogonadotrophic hypogonadism and characterization of novel mutations: a single-centre study.

STUDY QUESTION: What is the exact prevalence of Kisspeptin Receptor (KISS1R) mutations in the population of patients with normosmic congenital hypogonadotrophic hypogonadism (nCHH) by comparison with other genes, involved in gonadotrophin-releasing hormone (GnRH) release or action? SUMMARY ANSWER: KISS1R mutants are responsible for the nCHH phenotype in only a small minority of cases and were less prevalent than GnRH Receptor (GNRHR) mutations. WHAT IS KNOWN ALREADY: The respective prevalence of each of the genetic causes of nCHH is unclear. Large series of patients are very rare and suffer from heterogeneity of the population of CHH studied. STUDY DESIGN, SIZE, DURATION: Patients with nCHH were consecutively enrolled in a single French referral centre and were gradually tested for KISS1R between January 2006 and April 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 603 patients with nCHH (399 men and 204 women) were diagnosed at the Bicêtre Hospital and underwent KISS1R analysis. The GNRHR, tachykinin receptor 3 (TACR3), gonadotrophin-releasing hormone 1 (GNRH1), tachykinin 3 (TAC3) and KISS1 genes were also sequenced. Functional characterization of KISS1R mutations included a study of signal transduction using a reporter gene (serum response element-luciferase (SRE-Luc) involved in the mitogen-activated protein (MAP) kinase pathway. MAIN RESULTS AND THE ROLE OF CHANCE: We detected 15 KISS1R variants (10 novel), in 12 of the 603 patients (2.0%, 95% CI [0.9-3.1]. KISS1R mutations were less prevalent than GNRHR (4.7%) and TACR3 (2.6%) mutations but more prevalent than GNRH1 (1.5%), TAC3 (1.0%) and KISS1 (0%) mutations. KISS1R mutants were present in the biallelic state in 8 of the 12 patients concerned. Among 5 men with biallelic KISS1R mutations, 4 had either micropenis or cryptorchidism. In vitro analysis of the 5 new variants present in the biallelic state (C95W, Y103*, C115W, P176R and A287E) showed a loss of function. LIMITATIONS, REASONS FOR CAUTION: The prevalence of TACR3, GNRH1, TAC3 and KISS1 mutations was calculated from a smaller number of nCHH patients than KISS1R and GNRHR. This should prompt caution concerning the reported prevalence of mutations in these four genes. WIDER IMPLICATIONS OF THE FINDINGS: We show that KISS1R mutants are responsible for the nCHH phenotype in only a small minority of cases. Together, the genes analysed here were mutated in fewer than 15% of patients, suggesting a role of other genes in nCHH. The presence of cryptorchidism and/or micropenis in the majority of men with biallelic KISS1R mutations strongly suggests that this gene is essential for prenatal GnRH secretion. STUDY FUNDING, COMPETING INTERESTS: This work was supported in part by grants from Paris-Sud University (Bonus Qualité Recherche, and Attractivité grants) to J.B., French Ministry of Health, Hospital Clinical Research Program on Rare Diseases. Assistance Publique Hôpitaux de Paris, Programme Hospitalier de Recherche Clinique (PHRC # P081212 HYPOPROTEO) to J.Y. C.P. was supported by student fellowships 'Année Recherche' from Agence Régionale de Santé Provence Alpes Côtes d'Azur. The authors have nothing to disclose.

The Rationalization of Unethical Research: Revisionist Accounts of the Tuskegee Syphilis Study and the New Zealand "Unfortunate Experiment".

Two studies, widely condemned in the 1970s and 1980s-the Tuskegee study of men with untreated syphilis and the New Zealand study of women with untreated carcinoma in situ of the cervix-received new defenses in the 21st century. We noted remarkable similarities in both the studies and their defenses. Here we evaluate the scientific, political, and moral claims of the defenders. The scientific claims are largely based on incomplete or misinterpreted evidence and exaggeration of the uncertainties of science. The defenders' political arguments mistakenly claim that identity politics clouded the original critiques; in fact such politics opened the eyes of the public to exploitation. The moral defenses demonstrate an overreliance on codes of conduct and have implications for research ethics today.

Simvastatin dose and risk of rhabdomyolysis: nested case-control study based on national health and drug dispensing data.

BACKGROUND: Two randomised controlled trials have found a higher risk of rhabdomyolysis in users of 80 mg versus 20 mg simvastatin, but there is very limited information about the risk associated with other doses. We undertook a nested case-control study, using routinely collected national health and drug dispensing data, to estimate the relative and absolute risks of rhabdomyolysis resulting in hospital admission or death according to simvastatin dose. METHODS AND RESULTS: The underlying study cohort comprised all patients (n=313,552) who initiated a new episode of simvastatin use in New Zealand between 1 May 2005 and 31 December 2009. Cases (n=29) were patients with a diagnosis of rhabdomyolysis after cohort entry, confirmed by hospital discharge letter or death records. Ten controls, matched by year of birth and sex, were randomly selected from the study cohort using risk set sampling. Current users of 40 mg simvastatin daily were about five times as likely to develop rhabdomyolysis as those taking 20mg; the adjusted odds ratio was 5.3 (95% CI 1.9-15.0). The absolute excess risk of rhabdomyolysis associated with the use of 40 mg versus 20mg was about 10 per 100,000 person-years; the crude incidence rates were 11.5 (95% CI 7.1-17.5) and 2.1 (95% CI 0.7-4.8) per 100,000 person-years respectively. CONCLUSIONS: These findings provide reassurance that the absolute risk of rhabdomyolysis in a general population of simvastatin users is very low. Nonetheless, they also raise questions about the optimal simvastatin regimen to maximise cardiovascular benefits and minimise the risk of serious muscle injury.

A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use.

The magnitude of the suspected increase in risk of acute interstitial nephritis among proton pump inhibitor users is uncertain. Here, we conducted a nested case-control study using routinely collected national health and drug dispensing data in New Zealand to estimate the relative and absolute risks of acute interstitial nephritis resulting in hospitalization or death in users of proton pump inhibitors. The cohort included 572,661 patients without a history of interstitial nephritis or other renal diseases who started a new episode of proton pump inhibitor use between 2005 and 2009. Cases had a first diagnosis after cohort entry of acute interstitial nephritis confirmed by hospital discharge letter or death record, and renal histology (definite, 46 patients), or discharge letter or death record only (probable, 26 patients). Ten controls, matched by birth year and sex, were randomly selected for each case. In the case-control analysis based on definite cases and their controls, the unadjusted matched odds ratio (95% confidence interval) for current versus past use of proton pump inhibitors was 5.16 (2.21-12.05). The estimate was similar when all cases (definite and probable) and their corresponding controls were analyzed, and when potential confounders were added to the models. The crude incidence rates and confidence intervals per 100,000 person-years were 11.98 (9.11-15.47) and 1.68 (0.91-2.86) for current and past use, respectively. Thus, current use of a proton pump inhibitor was associated with a significantly increased risk of acute interstitial nephritis, relative to past use.

HSV-2 incidence by sex over four age periods to age 38 in a birth cohort.

OBJECTIVES: To examine herpes simplex virus type 2 (HSV-2) incidence over four periods to age 38 in a birth cohort, and to compare risks for men and women, taking into account sexual behaviour. METHODS: At ages 21, 26, 32 and 38, participants in the Dunedin Multidisciplinary Health and Development Study were invited to provide serum for HSV-2 serology, and information on sexual behaviour. HSV-2 incidence rates were calculated for four age periods, and comparisons made by sex and period, taking into account number of sexual partners. RESULTS: By age 38, 17.3% of men and 26.8% of women had ever been seropositive for HSV-2. Incidence peaked for women from age 21 to 26 (19.1 per 1000 person-years) and men from age 26 to 32 (14.1 per 1000 person-years); it fell markedly for both from age 32 to 38 (5.1 and 6.8 per 1000 person-years for men and women, respectively). Overall risk was significantly higher for women: adjusted incidence rate ratio 1.9 (95% CI 1.4 to 2.7); the sex difference was most marked from age 21 to 26 (3.4, 95% CI 1.9 to 6.3). CONCLUSIONS: Our findings are consistent with a greater biological susceptibility to HSV-2 among women, and with the increasing risk to the early/mid-20s for women and late 20s/early 30s for men, being driven by an increasing pool of prevalent infection. The reduced risk in the mid-30s is consistent with declining infectivity of long-term prevalent infections.

Do different types of financial support after illness or injury affect socio-economic outcomes? A natural experiment in New Zealand.

BACKGROUND: In New Zealand, people unable to work due to an illness may be eligible for a means-tested benefit whereas injured people are eligible for a wide range of support including earnings-related compensation through the no-fault Accident Compensation Corporation (ACC). The effect of this difference on socio-economic outcomes has not been investigated before. METHODS: A comparative cohort study was undertaken of stroke versus injury. Individuals aged 18-64, who had a first-stroke (n = 109) were matched by age, sex and functional impairment with injured individuals (n = 429) participating in the Prospective Outcomes of Injury Study. Data were collected by interview 3.5 and 12 months after stroke or injury. Logistic regression adjusting for the matching variables at 3.5 months, and functional impairment at 12 months, was undertaken. RESULTS: Median personal income declined by 60% over 12 months for the Stroke Group compared to 13% decline in the Injury Group. Decline in income was greater for those in both groups who had a higher income initially, and for those who had not returned to work. The proportion of the Stroke Group reporting 'Fairly low/low' standard of living increased from 8% to 28% and 'Just/not enough' income increased from 35% to 61% whereas the Injury Group increased only from 5% to 12% and 33%-44% respectively. The odds of reporting low standard of living and income inadequacy at 12 months were significantly less for the Injury Group. Despite earnings-related compensation (80% of income), the odds of being back at work were greater for the Injury Group compared to the Stroke Group (Adjusted Odds Ratio 3.1; 95% CI 1.7-5.6). CONCLUSIONS: These findings support the conclusions that earnings-related compensation and rehabilitative support, available to injured people via ACC, largely prevents the downward spiral into poverty and ill health. It also appears to enhance return to work though residual confounding cannot be ruled out.

Stability and change in same-sex attraction, experience, and identity by sex and age in a New Zealand birth cohort.

Gaps remain in knowledge of changes in sexual orientation past adolescence and early adulthood. A longitudinal study of a New Zealand birth cohort was used to examine differences by age and sex in change in sexual attraction between 21 (1993/1994) and 38 years (2010/2011), sexual experiences between 26 and 38 years, and sexual identity between 32 and 38 years. Any same-sex attraction was significantly more common among women than men at all ages. Among women, any same-sex attraction increased up to age 26 (from 8.8 to 16.6 %), then decreased slightly by age 38 (12.0 %); among men, prevalence was significantly higher at age 38 (6.5 %) than 21 (4.2 %), but not in the intermediate assessments. It is likely that the social environment becoming more tolerant was responsible for some of the changes. Same-sex attraction was much more common than same-sex experiences or a same-sex identity, especially among women, with no major sex differences in these latter dimensions. Women exhibited much greater change in sexual attraction between assessments than men; for change in experiences and identity, sex differences were less marked and not statistically confirmed. Changes in the respective dimensions appeared more likely among those initially with mixed attraction and experiences, and among those initially identifying as bisexual, but this did not account for the sex difference in likelihood of change. These results provide contemporary information about the extent and variation of reported sexual attraction, experiences, and identity that we show continues across early and mid-adulthood.

The relationship between multiple sex partners and anxiety, depression, and substance dependence disorders: a cohort study.

Changes in sexual behavior have resulted in longer periods of multiple serial or concurrent relationships. This study investigated the effects of multiple heterosexual partners on mental health, specifically, whether higher numbers of partners were linked to later anxiety, depression, and substance dependency. Data from the Dunedin Multidisciplinary Health and Development Study, a prospective, longitudinal study of a birth cohort born in 1972-1973 in Dunedin, New Zealand were used. The relationship between numbers of sex partners over three age periods (18-20, 21-25, and 26-32 years) and diagnoses of anxiety, depression, and substance dependence disorder at 21, 26, and 32 years were examined, using logistic regression. Interaction by gender was examined. Adjustment was made for prior mental health status. There was no significant association between number of sex partners and later anxiety and depression. Increasing numbers of sex partners were associated with increasing risk of substance dependence disorder at all three ages. The association was stronger for women and remained after adjusting for prior disorder. For women reporting 2.5 or more partners per year, compared to 0-1 partners, the adjusted odd ratios (and 95 % CIs) were 9.6 (4.4-20.9), 7.3 (2.5-21.3), and 17.5 (3.5-88.1) at 21, 26, and 32 years, respectively. Analyses using new cases of these disorders showed similar patterns. This study established a strong association between number of sex partners and later substance disorder, especially for women, which persisted beyond prior substance use and mental health problems more generally. The reasons for this association deserve investigation.

Drug safety awareness in New Zealand: public knowledge and preferred sources for information.

INTRODUCTION: To make informed choices about medical treatment options, patients and consumers need knowledge about the benefits and the risks of drugs. Little is known about levels of drug safety knowledge or preferred sources of drug safety information in general population samples. AIM: To explore drug safety knowledge, experience of adverse drug reactions (ADRs), and preferred sources for drug safety information in the New Zealand public. METHODS: We undertook a telephone survey of a random sample of adults (N=87) in the Dunedin area of New Zealand. RESULTS: Although 47% of those currently or recently using prescription or over-the-counter drugs (N=83) were unable to recall any safety information at all about the medicine they were taking, 84% felt confident they could use these medicines in a safe way. The experience of at least one ADR during the last five years was reported by 40%. The five most preferred sources for drug safety information among all participants were: doctor (92%), pharmacist (76%), information on/inside the medicine package (66%), nurse (57%), and the internet (41%). DISCUSSION: Our results add to findings from specific patient groups to show that there is a low level of drug safety knowledge in the general population. Primary health care practitioners have a recognised and vital part to play in promoting drug safety awareness.

The destination of Pacific Island health professional graduates from a New Zealand university.

BACKGROUND: There is a shortage of health professionals in Pacific Island states and territories, and a need in New Zealand for Pacific health professionals to serve Pacific communities. METHODS: A cross-sectional postal survey was conducted to investigate retention of Pacific graduates. All graduates of Pacific ethnicity or nationality from the University of Otago in the years 1994 to 2004 in medicine, dentistry, pharmacy, physiotherapy and medical laboratory science were included. RESULTS: The response rate was 59% (75 out of 128). Only 7% of respondents were working in the Pacific Islands (12% of non-residents and 4% of New Zealand residents), though the proportion in the whole cohort could be up to 20%. One third intended to work in Pacific communities in New Zealand or the Pacific Islands in the future. Factors that would favour such an intention were an adequate income, job availability, and good working conditions. CONCLUSIONS: Retention of graduates in the Pacific Islands is poor and measures to improve retention are needed.

Traumatic and non-traumatic spinal cord impairment in New Zealand: incidence and characteristics of people admitted to spinal units.

This paper estimates the incidence (all ages) of spinal cord neurological impairment (SCI; traumatic and non-traumatic) in New Zealand and describes pre-SCI characteristics and early post-SCI outcomes for participants (16-64 years) in this longitudinal study. Demographic and clinical data on all people admitted to New Zealand's two spinal units (mid-2007 to mid-2009) were included for the estimate of incidence. Participants in this longitudinal study were asked at first interview about pre-SCI socio-demographic, health and behavioural characteristics, and about post-SCI symptoms, general health status (EQ-5D) and disability (WHODAS 12-item). Age-adjusted incidence rates (95% CI) for European, Maori, Pacific and 'Other' ethnicities were 29 (24-34), 46 (30-64), 70 (40-100) and 16 (9-22) per million, respectively. Interviews with 118 (73%) participants (16-64 years), occurred 6.5 months post-SCI. Most reported bother with symptoms, and problems with health status and disability. Compared with Europeans, the incidence of SCI is high among Maori and particularly high among Pacific people. Six months after SCI, proximate to discharge from the spinal units, considerable symptomatic, general health and disability burden was borne by people with SCI.