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The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P= 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

AbstractThe current study tested the effectiveness of a compact (18 hour) and blended (involving online and face-to-face components) training course, adapted from a previously evaluated course found to be successful in fostering long-term change in interviewing skill. The compact course was developed by trimming the previous course to only include learning activities that empirically demonstrated improvement of interviewing skills. There were 41 US forensic interviewers, with prior training experience, who took part in the research. Their interviewing habits were assessed using standardized mock interviews immediately prior to, and at the conclusion of training. A subset were assessed 9-24 months later. Results demonstrated that, despite reductions in length and content, training was effective in the short term and the subset maintained trained behaviors up to 24 months after completion. Results suggest that adjustments to training can be effective if the training remains founded on principles of human learning.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84–5.29) for men of European ancestry to 3.74 (95% CI, 3.36–4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14–2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71–0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

IMPORTANCE: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. OBJECTIVE: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. MAIN OUTCOMES AND MEASURES: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. RESULTS: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier. CONCLUSIONS AND RELEVANCE: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

ABSTRACTHuman rights are increasingly being considered in Australian law reform and policy discussions on how to improve the circumstances of people living with dementia in care homes. This article enriches understanding of the views on human rights held by people living with dementia and those who support, advocate and care for them, in order to ensure that law and policy reforms that promote human rights can be meaningfully enjoyed in practice. Drawing on data from focus groups and interviews with people living with dementia, care partners, aged care workers, and lawyers and advocates, this article argues that there is general support among stakeholders for human rights. However, this support was qualified by their acknowledgement of entrenched economic, cultural and sociolegal barriers to the recognition of human rights in the everyday lives of people living with dementia. The article concludes that urgent action is required to transform the cultural, economic and social drivers of ambivalence and resistance to dementia and human rights within aged care and the broader community.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P< 5.0 × 10−8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P= 8.2 × 10−9; G>C, p.Pro1054Arg) in ATMand rs2066827 (OR = 1.06; P= 2.3 × 10−9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55–2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04–6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1. A large meta-analysis combining genome-wide and custom high-density genotyping array data identifies 63 new susceptibility loci for prostate cancer, enhancing fine-mapping efforts and providing insights into the underlying biology.

AbstractInternational and Australian domestic evidence suggest that the prevalence of violence against people with disability is substantially higher than for the rest of the community. Much of the violence experienced by people with disability in Australia occurs within the purview of a variety of institutions, including group homes, large residential institutions, Australian Disability Enterprises (that is, disability employment facilities), schools, psychiatric facilities, hospitals and correctional facilities. This comment discusses recent domestic and international legal and political attempts to grapple with the issue of institutional violence against people with disability, focusing in particular on a series of Senate Committee inquiries into abuse and violence, regulation related to the National Disability Insurance Scheme, the coming into force of the Convention on the Rights of Persons with Disabilities, Australia's anticipated ratification of the Optional Protocol to the Convention Against Tortureand recent calls by Disability People's Organisations and academics for a Royal Commission into violence against people with disability.

ABSTRACTIn 2017, Australia ratified the Optional Protocol to the Convention against Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment (OPCAT). Ratification of OPCAT presents as a unique opportunity to highlight the institutional treatment of people with disability in a range of sites of detention within Australia and build on advancing international protections for people with disability, including those articulated in the Convention on the Rights of Persons with Disabilities (CRPD). This article considers the opportunity presented by OPCAT for improving protections for people with disability against torture and ill-treatment. The article argues for an expansive definition of ‘sites of detention’ that is able to encapsulate both disability-specific and mainstream settings in which people with disability may be deprived of their liberty, as well as to address specific practices such as the use of mechanical restraint, chemical restraint and seclusion. Based on an analysis of international National Preventive Mechanism (NPM) models, it is further argued that people with disability, their representative bodies and other civil society actors must be meaningfully involved in NPM processes, including in the monitoring of sites of detention, and the identification of systemic issues affecting people with disability with lived experience of detention.

ABSTRACTA recent suggestion of some disability legal scholars is to provide a non-discriminatory legal framework to regulate non-consensual medical and care interventions in relation to disabled people through adapting the doctrine of necessity. This article rejects this approach through a close reading of the leading decision on the doctrine of necessity in medical and care settings, In re F (Mental Patient: Sterilization)[1990] 2 AC 1. This decision confirms that any such suggestion for the application of the doctrine will impact disabled people differentially due to divergent legal constructions of temporality between disabled and able people. To use this doctrine in relation to ongoing disabled medical and care interventions the law constructs disabled people as being in a permanent state of mental incapacity. On the other hand, the doctrine of necessity constructs able people as temporarily mentally incapacitated from their usual state of autonomy, thus only requiring minimal medical and care interventions to return them to their prior state. Therefore, able people cannot, under this doctrine, lawfully be subject to similarly long periods of intervention and such a broader range of interventions. Application of the doctrine of necessity will thus exacerbate inequality of and violence against disabled people.

This article analyses the place of the intersections of the criminal law of assault and the Family Court's welfare jurisdiction in rendering Family Court authorised sterilisation of girls with intellectual disability a legally permissible form of violence. The article does this by examining court authorised sterilisation of girls with intellectual disability by reference to the concepts of ‘legal violence’ and ‘abnormality’. The article's central argument is that Family Court authorised sterilisation of girls with intellectual disability is a form of lawful and ‘good’ violence against abnormal legal subjects. Such girls are – by reason of their incapacity – positioned outside the group of ‘normal’ legal subjects of assault who have the capacity to decide to consent to contact with their otherwise ‘impermeable’ and legally sacrosanct bodies. As the girls with intellectual disability are deemed to constitute ‘abnormal’ legal subjects of assault, the lawfulness of the contact involved in the act of their sterilisation is not dependent on the consent of the girls themselves, but instead on the consent of their parents as authorised by the Family Court acting in its welfare jurisdiction. In the course of authorising parental consent to sterilisation, the Family Court not only renders an act of sterilisation ‘lawful violence’, but also ‘good violence’ through the characterisation of girls with intellectual disability as absolutely different to individuals without disability, and through the characterisation of the act in legal, familial and medical terms.

This special issue of the Griffith Law Reviewis dedicated to an examination of the relationships and intersections between disability, criminal law and legal theory. Despite the centrality of disability to the doctrines, operation and reform of criminal law, disability continues to inhabit a marginal location in legal theoretical engagement with criminal law. This special issue proceeds from a contestation of disability as an individual, medical condition and instead explores disability's social, political and cultural contexts. This kind of approach directs critical attention to questioning many aspects of the relationships between disability and criminal law which have otherwise been taken for granted or overlooked in legal scholarship. These aspects include the differential treatment of people with disability by criminal law, the impact of core legal concepts such as capacity on criminal legal treatment of people with disability, and the role of disability in ordering and legitimising criminal law. It is hoped that the special issue will contribute to the shifting of disability from its peripheral location in legal theoretical scholarship much more to the centre of critical and political engagement with criminal law.

The purpose of this study was to determine patient and caregiver satisfaction with a hospice program of care. The setting for the study was a home-care hospice in the southeastern United States that provides a full range of services for patients with life-limiting illness and supportive services for family caregivers. Two Likert-type instruments were used to determine satisfaction with staff, communication, education, information provided, symptom management, promptness with service, and overall satisfaction. Some 321 patients and 443 caregivers completed surveys over a two-year period of time. Data indicates the majority of patients and their care-givers were very satisfied with hospice services and the care they received. Providing quality care at the end of life is the goal of hospice. Satisfaction with delivery of care, management of symptoms, and communication with staff are all components of quality care and contribute to quality of life.

Objective: Decreased insulin sensitivity and deterioration in oral glucose tolerance curves have been reported with oral contraceptive use, particularly with those containing levonorgestrel. However, the subdermal levonorgestrel systems release a lower dosage of steroid and avoid the first pass through the liver that occurs with oral administration. We hypothesized, therefore, that continuous subdermal levonorgestrel has no significant effect on insulin sensitivity and other indices of glucose metabolism. Methods: Nine women desiring a subdermal hormonal contraceptive system were recruited for this longitudinal prospective study. Each subject underwent a 3-hour frequently sampled intravenous glucose tolerance test immediately before insertion and after 6 months of continuous use. Insulin sensitivity and glucose effectiveness were determined using a mathematical minimal modeling approach. Glucose clearance and fasting and peak levels of glucose and insulin were examined as well. The matched-pair data were analyzed using paired ttests. Results: There was no significant change in insulin sensitivity, glucose effectiveness, glucose clearance, or fasting or peak insulin levels. Fasting glucose levels remained within a normal range. Conclusions: Subdermal levonorgestrel appears to have no significant effect on tissue insulin sensitivity or glucose metabolism after 6 months of continuous use.

Health care professionals employed in diverse settings are in an ideal situation to identify those bereaved spouses who may be at higher risk for developing physical and/or emotional problems related to the bereavement process. This study examined demographic variables and their relationship to behaviors associated with grief. Significant findings revealed that age, sex, socioeconomic status, and quality of relationship to the deceased are related to specific high-risk bereavement behaviors. The results of this study can be used to screen high-risk spouses.

No abstract.

Objective:Decreased insulin sensitivity and deterioration in oral glucose tolerance curves habe been reported with oral contraceptive use, particularly with those containing levonorgestrel. However, the subdermal levonorgestrel systems release a lower dosage of steriod and avoid the first pass through the liver that occurs with oral administration. We hypothesized, therefore, that continuous subdermal levonorgestrel has no significant effect on insulin sensitivity and other indices of glucose metabolism.Methods:Nine women desiring a subdermal hormonal contraceptive system were recruited for this longitudinal prospective study. Each subject underwent a 3-hour frequently sampled intravenous glucose tolerance test immediately before insertion and after 6 months of continuous ues. Insulin sensitivity and glucose effectiveness were determined using a mathematical minimal modeling approach. Glucose clearance and fasting and peak levels of glucose and insulin were examined as well. The matched-pair data were analzed using paired t tests.Results:There was no significant change in insulin sensitivity, glucose effectiveness, glucose clearance, or fasting or peak insulin levels. Fasting glucose levels remained within a normal range.Conclusions:Subdermal levonorgestrel appears to have no significant effects on tissue insulin sensitivity or glucose metabolism after 6 months of continuous use.

Circadian rhythms in physiological processes and behaviors were compared with hypothalamic circadian rhythms in norepinephrine (NE) metabolites, adrenergic transmitter receptors, cAMP, cGMP and suprachiasmatic nucleus (SCN) arginine vasopressin (AVP) in a single population of rats under D: D conditions. Eating, drinking and locomotor activity were high during the subjective night (the time when lights were out in L: D) and low during the subjective day (the time when lights were on in L: D). Plasma corticosterone concentration rose at subjective dusk and remained high until subjective dawn. Binding to hypothalamic α1- and β-adrenergic receptors also peaked during the subjective night. Cyclic cGMP concentration was elevated throughout the 24-hr period except for a trough at dusk, whereas DHPG concentration peaked at dawn. Arginine vasopressin levels in the suprachiasmatic nucleus peaked in the middle of the day. No rhythm was found either in binding to the α2-adrenergic receptor, or in MHPG or cAMP concentration. Behavioral and corticosterone rhythms, therefore, are parallel to rhythms in hypothalamic α1-and β-receptor binding and NE-release. Cyclic GMP falls only at dusk, suggesting the possibility that cGMP inhibits activity much of the day and that at dusk the inhibition of nocturnal activity is removed. SCN AVP, on the other hand, peaking at 1400 hr, may play a role in the pacemaking function of the SCN that drives these other rhythms.

Circadian rhythms in noradrenergic (NE) and dopaminergic (DA) metabolites and in cyclic nucleotide production were measured in discrete regions of rat brain. A circadian rhythm was found in the concentration of the NE metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), in the hippocampus. No MHPG rhythm was found in frontal, cingulate, parietal, piriform, insular or temporal cortex, or in hypothalamus. Circadian rhythms in the concentration of the NE metabolite, 3,4-dihydroxyphenylglycol (DHPG), occurred in occipital and parietal cortex and hypothalamus, with no rhythm observable in temporal or insular cortex, hippocampus, pons-medulla or cerebellum. The 24-hr mean concentration of MHPG varied 3.5-fold, highest in cingulate and lowest in parietal, temporal and occipital cortex. The 24-hr mean concentration of DHPG varied 6-fold, highest in hypothalamus and lowest in parietal cortex. Circadian rhythms in the concentration of the DA metabolite, homovanillic acid (HVA), were found in olfactory tubercle, amygdala and caudate-putamen, but not in nucleus accumbens. A circadian rhythm in the concentration of the DA metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), occurred in nucleus accumbens, but not in olfactory tubercle or caudate-putamen. The mean 24-hr concentration of HVA was highest in caudate-putamen, intermediate in nucleus accumbens, and lowest in olfactory tubercle and amygdala. The mean 24-hr concentration of DOPAC was highest in nucleus accumbens and lower in olfactory tubercle and caudate-putamen. Circadian rhythms were found in the concentration of cyclic GMP (cGMP) in all regions measured except parietal cortex. The mean 24-hr concentration varied 128-fold, highest in nucleus accumbens, frontal poles, and hypothalamus and lowest in cingulate cortex. Circadian rhythms in cyclic AMP (cAMP) concentration were found in piriform, temporal, occipital, cingulate, and parietal cortex, amygdala and nucleus accumbens. No rhythms were found in frontal or insular cortex, hypothalamus, hippocampus, caudate-putamen or olfactory tubercle. The 24-hr mean cAMP concentration varied 4-fold, highest in parietal cortex and lowest in caudate-putamen and amygdala. Norepinephrine metabolites and dopamine metabolites were rhythmic in few regions. It is, therefore, unlikely that the rhythmicity measured in adrenergic receptors is, in general, a response to rhythmic changes in adrenergic transmitter release. The putative second messenger response systems, especially cGMP, were more often rhythmic. The rhythms in cGMP are parallel in form and region to those in the α1-adrenergic receptor and may act as 2nd messenger for that receptor. In vivo, only the rhythm in cAMP in cingulate cortex parallels changes in the α1-adrenergic receptor, even though rhythms in cAMP in vitro can reflect rhythms in cortical α1- and β-receptor number. Cyclic AMP rhythms probably represent a summation of stimulatory and inhibitory transmitter receptor actions, perhaps modified by rhythms in the adenylate cyclase complex and its substrates.

A Correction to this paper has been published: https://doi.org/10.1038/s41588-021-00786-2.

Describes Edmonton Telephones Corp.'s Talking Yellow Pages directory. Categories of the directory; Success of the directory's Talking Community Pages service; Company's promotional efforts; Reason for the Community Pages' success.

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.