Protocol for the TRANSLATE prospective, multicentre, randomised clinical trial of prostate biopsy technique.

OBJECTIVES: Primary objectives: to determine whether local anaesthetic transperineal prostate (LATP) biopsy improves the detection of clinically significant prostate cancer (csPCa), defined as International Society of Urological Pathology (ISUP) Grade Group ≥2 disease (i.e., any Gleason pattern 4 disease), compared to transrectal ultrasound-guided (TRUS) prostate biopsy, in biopsy-naïve men undergoing biopsy based on suspicion of csPCa. SECONDARY OBJECTIVES: to compare (i) infection rates, (ii) health-related quality of life, (iii) patient-reported procedure tolerability, (iv) patient-reported biopsy-related complications (including bleeding, bruising, pain, loss of erectile function), (v) number of subsequent prostate biopsy procedures required, (vi) cost-effectiveness, (vii) other histological parameters, and (viii) burden and rate of detection of clinically insignificant PCa (ISUP Grade Group 1 disease) in men undergoing these two types of prostate biopsy. PATIENTS AND METHODS: The TRANSLATE trial is a UK-wide, multicentre, randomised clinical trial that meets the criteria for level-one evidence in diagnostic test evaluation. TRANSLATE is investigating whether LATP biopsy leads to a higher rate of detection of csPCa compared to TRUS prostate biopsy. Both biopsies are being performed with an average of 12 systematic cores in six sectors (depending on prostate size), plus three to five target cores per multiparametric/bi-parametric magnetic resonance imaging lesion. LATP biopsy is performed using an ultrasound probe-mounted needle-guidance device (either the 'Precision-Point' or BK UA1232 system). TRUS biopsy is performed according to each hospital's standard practice. The study is 90% powered to detect a 10% difference (LATP biopsy hypothesised at 55% detection rate for csPCa vs 45% for TRUS biopsy). A total of 1042 biopsy-naïve men referred with suspected PCa need to be recruited. CONCLUSIONS: This trial will provide robust prospective data to determine the diagnostic ability of LATP biopsy vs TRUS biopsy in the primary diagnostic setting.

Splenic erythroid progenitors decrease TNF-α production by macrophages and reduce systemic inflammation in a mouse model of T cell-induced colitis.

In inflammatory bowel disease (IBD), inflammation can occur beyond the intestine and spread systemically causing complications such as arthritis, cachexia, and anemia. Here, we determine the impact of CD45, a pan-leukocyte marker and tyrosine phosphatase, on IBD. Using a mouse model of T cell transfer colitis, CD25- CD45RBhigh CD4+ T cells were transferred into Rag1-deficient mice (RAGKO) and CD45-deficient RAGKO mice (CD45RAGKO). Weight loss and systemic wasting syndrome were delayed in CD45RAGKO mice compared to RAGKO mice, despite equivalent inflammation in the colon. CD45RAGKO mice had reduced serum levels of TNF-α, and reduced TNF-α production by splenic myeloid cells. CD45RAGKO mice also had increased numbers of erythroid progenitors in the spleen, which had previously been shown to be immunosuppressive. Adoptive transfer of these erythroid progenitors into RAGKO mice reduced their weight loss and TNF-α expression by splenic red pulp macrophages. In vitro, erythroid cells suppressed TNF-α expression in red pulp macrophages in a phagocytosis-dependent manner. These findings show a novel role for erythroid progenitors in suppressing the pro-inflammatory function of splenic macrophages and cachexia associated with IBD.

The effect of rapid exome sequencing on downstream health care utilization for infants with suspected genetic disorders in an intensive care unit.

PURPOSE: This study aimed to compare downstream utilization of medical services among critically ill infants admitted to intensive care units who received rapid exome sequencing (ES) and those who followed alternative diagnostic testing pathways. METHODS: Using propensity score-weighted regression models including sex, age at admission, and severity indicators, we compared a group of 47 infants who underwent rapid ES with a group of 211 infants who did not receive rapid ES. Utilization and cost indicators were compared between cohorts using negative binomial models for utilization and two-part models for costs. RESULTS: After controlling for patients' sociodemographic and clinical characteristics, we found no statistically significant difference in outpatient visits, hospitalizations, intensive care unit or total length of stay, or length of stay-associated costs between the cohorts at 12- or 26-month follow-up. Similarly, there was no evidence of higher utilization or costs by the ES group when infants who died were removed from the analysis. CONCLUSION: When examining utilization during and beyond the diagnostic trajectory, there is no evidence that ES changes frequency of outpatient visits or use of in-hospital resources in critically ill infants with suspected genetic disorders.

Implementing genomics in the neonatal period: An assessment of parental decision making and anxiety.

As uptake of rapid genome sequencing (GS) in the neonatal period steadily increases, a clinical genetics service that is optimized to the needs of parents becomes increasingly important. We aimed to investigate factors that influence decision making about rapid GS by parents of infants admitted to neonatal intensive care units (NICU) and explore their experiences of decisional conflict and anxiety during this time. Parents of neonates suspected of having a genetic disorder and offered rapid GS in the NICU completed a questionnaire measuring experience with GS counseling, decisional conflict, and anxiety level. Our results demonstrate that despite a largely positive GS experience (70%; 21/30) among the survey respondents, 50.0% (14/28) experienced moderate to severe anxiety measured using the GAD-7 scale, and 34.6% (9/26) experienced decisional conflict measured using the SURE scale. We also showed that prematurity may be a modifier of anxiety in this group of parents and although not statistically significant, distance lived away from the hospital site could have practical significance. Open-ended responses to survey questions highlighted that feeling overwhelmed, the types of engagements parents had with healthcare providers, and the timing of information provision also influenced parental decision making in this setting. We suggest that the GAD-7 scale for generalized anxiety and SURE scale for decisional conflict could be incorporated by genetic counselors into routine care of parents of neonates who have been offered rapid GS to identify those who may need additional support (resources, information, or psychological). These tools may inform ways that communication between patients and providers can be improved and enhanced and clinical genetics services in the NICU can be optimized. We suggest that integrating genetic counselors into the NICU care team could increase access for this population and ensure delivery of optimized patient education and counseling.

Mitochondrial genome variant m.3250T>C as a possible risk factor for mitochondrial cardiomyopathy.

The MT-TL1 gene codes for the mitochondrial leucine transfer RNA (tRNALeu(UUR) ) necessary for mitochondrial translation. Pathogenic variants in the MT-TL1 gene result in mitochondriopathy in humans. The m.3250T>C variant in the MT-TL1 gene has been previously associated with exercise intolerance and mitochondrial myopathy, yet disease classification for this variant has not been consistently reported. Molecular studies suggest the m.3250T>C variant does not alter tRNALeu(UUR) structure but may have a modest impact on aminoacylation capacity. However, functional studies are limited. Our study aimed to further define the clinical presentation, inheritance pattern, and molecular pathology of the m.3250T>C variant. Families with the m.3250T>C variant were recruited from the Mitochondrial Disease Clinic at Cincinnati Children's Hospital Medical Center and GeneDx laboratory database. Affected individuals most frequently presented with cardiac findings, exercise intolerance, and muscle weakness. Hypertrophic cardiomyopathy was the most frequent cardiac finding. Many asymptomatic individuals had homoplasmic or near homoplasmic levels of the m.3250T>C variant, suggesting the penetrance is incomplete. Patient-derived fibroblasts demonstrated lowered ATP production and increased levels of reactive oxygen species. Our results demonstrate that the m.3250T>C variant exhibits incomplete penetrance and may be a possible cause of cardiomyopathy by impacting cellular respiration in mitochondria.

Support, information, and integration of genetics for children with congenital lower limb deficiencies in British Columbia, Canada.

OBJECTIVES: Children and families affected by congenital limb deficiencies (CLD) require a unique level of emotional support from diagnosis through to adolescence. The following study aims to collect data on Canadian paediatric patients affected by a CLD followed at BC Children's Hospital (BCCH), Department of Orthopaedics. METHODS: Parents of children with a CLD were asked to complete a written questionnaire examining their experiences. Qualitative and quantitative data were collected concerning parent satisfaction with patient referrals, emotional support, and knowledge of their child's diagnosis. RESULTS: Twenty-five completed questionnaires were returned. Fifty per cent of the parents reported they were either very satisfied, or satisfied, with the emotional support provided by health care providers (HCPs). Twenty-five per cent of the parents were unsatisfied with the emotional support received by HCPs. Forty-eight per cent of the parents could not recall the specific name of their child's diagnosis; 20% of the parents reported their child did not have diagnosis. All the patients in our study had received a clinical diagnosis. Twenty-eight per cent of the parents in this study were also seen in medical genetics. CONCLUSIONS: Families require additional resources for emotional support, peer support, and referrals to support organizations. Gaps in parent knowledge regarding their child's CLD suggest the need for formalized communication strategies for HCPs. Furthermore, patients with CLDs and their families may benefit from improved communication between orthopaedic and medical genetic services at the time of diagnosis. Integration of genetic counsellors may improve emotional supports and education for families with regards to testing and reproductive planning.

Mentoring the Mentors of Underrepresented Racial/Ethnic Minorities Who are Conducting HIV Research: Beyond Cultural Competency.

The majority of literature on mentoring focuses on mentee training needs, with significantly less guidance for the mentors. Moreover, many mentoring the mentor models assume generic (i.e. White) mentees with little attention to the concerns of underrepresented racial/ethnic minorities (UREM). This has led to calls for increased attention to diversity in research training programs, especially in the field of HIV where racial/ethnic disparities are striking. Diversity training tends to address the mentees' cultural competency in conducting research with diverse populations, and often neglects the training needs of mentors in working with diverse mentees. In this article, we critique the framing of diversity as the problem (rather than the lack of mentor consciousness and skills), highlight the need to extend mentor training beyond aspirations of cultural competency toward cultural humility and cultural safety, and consider challenges to effective mentoring of UREM, both for White and UREM mentors.

FDXR variants cause adrenal insufficiency and atypical sexual development.

Genetic defects affecting steroid biosynthesis cause cortisol deficiency and differences of sex development; among them recessive mutations in the steroidogenic enzymes CYP11A1 and CYP11B, whose function is supported by reducing equivalents donated by ferredoxin reductase (FDXR) and ferredoxin. So far, mutations in the mitochondrial flavoprotein FDXR have been associated with a progressive neuropathic mitochondriopathy named FDXR-Related Mitochondriopathy (FRM), but cortisol insufficiency has not been documented. However, FRM patients often experience worsening or demise following stress associated with infections. We investigated two female FRM patients carrying the novel homozygous FDXR mutation p.G437R with ambiguous genitalia at birth and sudden death in the first year of life; they presented with cortisol deficiency and androgen excess compatible with 11-hydroxylase deficiency. In addition, steroidogenic FDXR-variant cell lines reprogrammed from three FRM patients' fibroblasts displayed deficient mineralocorticoid and glucocorticoid production. Finally, Fdxr-mutant mice allelic to the severe p.R386W human variant, showed reduced progesterone and corticosterone production. Therefore, our comprehensive studies show that human FDXR variants may cause compensated, but possibly life-threatening adrenocortical insufficiency in stress by affecting adrenal glucocorticoid and mineralocorticoid synthesis through direct enzyme inhibition, most likely in combination with disturbed mitochondrial redox balance.

Utilization of telehealth in paediatric genome-wide sequencing: Health services implementation issues in the CAUSES Study.

INTRODUCTION: Genome-wide sequencing (exome or whole genome) is transforming the care and management of paediatric patients with a rare disease because of its diagnostic capabilities. Genome-wide sequencing is most effective when both parents and the child are sequenced as a trio. Genetic counselling is recommended for all families considering genome-wide sequencing. Although telehealth is well established in genetic counselling for hereditary cancer and prenatal genetics, its use with genome-wide sequencing has not been well studied. The CAUSES Clinic at BC Children's and Women's Hospitals was a translational paediatric trio-based genome-wide sequencing initiative. Pre-test genetic counselling via telehealth (at a clinical site near the family's residence) was offered to families who had been previously evaluated by a clinical geneticist. We report on the first 300 families seen in the CAUSES clinic and compare health services implementation issues of families seen via telehealth versus on-site. METHODS: Demographics, cost to families (travel and time), time to first appointment, complete trio sample accrual and diagnostic rates were studied. RESULTS: Of the 300 patients, 58 (19%) were seen via telehealth and 242 (81%) were seen on-site for pre-test counselling. The mean time to completion of accrual of trio samples in the telehealth group was 56.3 (standard deviation ±87.3) days versus 18.9 (standard deviation ±62.4) days in the onsite group (p < 2.2 × 10-16). The mean per-family estimated actual or potential travel/time cost savings were greater in the telehealth group (Can$987; standard deviation = Can$1151) than for those seen on-site (Can$305; standard deviation = Can$589) (p = 0.0004). CONCLUSIONS: Telehealth allowed for access to genome-wide sequencing for families in remote communities and for them to avoid significant travel and time costs; however, there was a significant delay to accrual of the complete trio samples in the telehealth group, impacting on time of result reporting and delaying diagnoses for families for whom genome-wide sequencing was diagnostic.

Indian boarding school experience, substance use, and mental health among urban two-spirit American Indian/Alaska natives.

BACKGROUND: Systematic efforts of assimilation removed many Native children from their tribal communities and placed in non-Indian-run residential schools. OBJECTIVES: To explore substance use and mental health concerns among a community-based sample of 447 urban two-spirit American Indian/Alaska Native adults who had attended boarding school as children and/or who were raised by someone who attended boarding school. METHOD: Eighty-two respondents who had attended Indian boarding school as children were compared to respondents with no history of boarding school with respect to mental health and substance use. RESULTS: Former boarding school attendees reported higher rates of current illicit drug use and living with alcohol use disorder, and were significantly more likely to have attempted suicide and experienced suicidal thoughts in their lifetime compared to non-attendees. About 39% of the sample had been raised by someone who attended boarding school. People raised by boarding school attendees were significantly more likely to have a general anxiety disorder, experience posttraumatic stress disorder symptoms, and have suicidal thoughts in their lifetime compared to others.

Finding middle ground: negotiating university and tribal community interests in community-based participatory research.

Community-based participatory research (CBPR) has been hailed as an alternative approach to one-sided research endeavors that have traditionally been conducted on communities as opposed to with them. Although CBPR engenders numerous relationship strengths, through its emphasis on co-sharing, mutual benefit, and community capacity building, it is often challenging as well. In this article, we describe some of the challenges of implementing CBPR in a research project designed to prevent cardiovascular disease among an indigenous community in the Pacific Northwest of the United States and how we addressed them. Specifically, we highlight the process of collaboratively constructing a Research Protocol/Data Sharing Agreement and qualitative interview guide that addressed the concerns of both university and tribal community constituents. Establishing these two items was a process of negotiation that required: (i) balancing of individual, occupational, research, and community interests; (ii) definition of terminology (e.g., ownership of data); and (iii) extensive consideration of how to best protect research participants. Finding middle ground in CBPR requires research partners to examine and articulate their own assumptions and expectations, and nurture a relationship based on compromise to effectively meet the needs of each group.

Project həli?dx(w)/Healthy Hearts Across Generations: development and evaluation design of a tribally based cardiovascular disease prevention intervention for American Indian families.

American Indian and Alaska Native (AIAN) populations are disproportionately at risk for cardiovascular disease (CVD), diabetes, and obesity, compared with the general US population. This article describes the həli?dx(w)/Healthy Hearts Across Generations project, an AIAN-run, tribally based randomized controlled trial (January 2010-June 2012) designed to evaluate a culturally appropriate CVD risk prevention program for AI parents residing in the Pacific Northwest of the United States. At-risk AIAN adults (n = 135) were randomly assigned to either a CVD prevention intervention arm or a comparison arm focusing on increasing family cohesiveness, communication, and connectedness. Both year-long conditions included 1 month of motivational interviewing counseling followed by personal coach contacts and family life-skills classes. Blood chemistry, blood pressure, body mass index, food intake, and physical activity were measured at baseline and at 4- and 12-month follow-up times.

Mitochondrial Genome Variants as a Cause of Mitochondrial Cardiomyopathy.

Mitochondria are small double-membraned organelles responsible for the generation of energy used in the body in the form of ATP. Mitochondria are unique in that they contain their own circular mitochondrial genome termed mtDNA. mtDNA codes for 37 genes, and together with the nuclear genome (nDNA), dictate mitochondrial structure and function. Not surprisingly, pathogenic variants in the mtDNA or nDNA can result in mitochondrial disease. Mitochondrial disease primarily impacts tissues with high energy demands, including the heart. Mitochondrial cardiomyopathy is characterized by the abnormal structure or function of the myocardium secondary to genetic defects in either the nDNA or mtDNA. Mitochondrial cardiomyopathy can be isolated or part of a syndromic mitochondrial disease. Common manifestations of mitochondrial cardiomyopathy are a phenocopy of hypertrophic cardiomyopathy, dilated cardiomyopathy, and cardiac conduction defects. The underlying pathophysiology of mitochondrial cardiomyopathy is complex and likely involves multiple abnormal processes in the cell, stemming from deficient oxidative phosphorylation and ATP depletion. Possible pathophysiology includes the activation of alternative metabolic pathways, the accumulation of reactive oxygen species, dysfunctional mitochondrial dynamics, abnormal calcium homeostasis, and mitochondrial iron overload. Here, we highlight the clinical assessment of mtDNA-related mitochondrial cardiomyopathy and offer a novel hypothesis of a possible integrated, multivariable pathophysiology of disease.

Regulation of CD71+TER119+ erythroid progenitor cells by CD45.

Red blood cells are generated daily to replenish dying cells and maintain erythrocyte homeostasis. Erythropoiesis is driven by erythropoietin and supported by specialized red pulp macrophages that facilitate enucleation. Here we show that the leukocyte-specific tyrosine phosphatase CD45 is downregulated in late erythroid development, yet it regulates the CD71+TER119+ progenitor pool, which includes the Pro E, Ery A, and Ery B populations. The CD71+TER119+ progenitors are a major splenic population in neonates required for extramedullary erythropoiesis, to meet the high demand for red blood cells during growth. This population decreases as the mice mature, but this was not the case in CD45-deficient mice, which maintained a high level of these progenitors in the spleen into adulthood. Despite these increased erythroid progenitors, CD45-deficient mice had normal numbers of mature red blood cells. This was attributed to the increased proliferation of the Pro E and Ery A populations and the increased apoptosis of the CD71+TER119+ population, as well as an increased turnover of circulating red blood cells. The expansion of the CD71+TER119+ population in the absence of CD45 was attributed to increased numbers of red pulp macrophages producing erythropoietin in the spleen. Thus, CD45 regulates extramedullary erythropoiesis in the spleen.

Assessing Health Provider Perspectives Regarding Barriers American Indian/Alaska Native Transgender and Two-Spirit Youth Face Accessing Healthcare.

BACKGROUND: American Indian/Alaska Native (AI/AN) youth disproportionately face barriers accessing healthcare compared with non-AI/AN youth. AI/AN youth who also identify as transgender or Two-Spirit (2S) face higher rates of mental health issues and suicidality, along with increased rates of disease, due to health inequity and historical trauma. OBJECTIVES: This project evaluated health provider knowledge of context surrounding gender and sexuality in AI/AN communities. It assessed provider perspectives of provider-side and patient-side barriers accessing care to develop suggestions for improvement. METHODS: Semi-structured interviews (SSI) and focus group discussions (FGD) were held among healthcare providers across four sites in the Pacific Northwest. Questions were developed using a community-based participatory research conceptual model, considering the impacts of context, partnerships, and community knowledge. A grounded theory approach was used to analyze transcripts. This project received exemption from the University of Washington IRB and approval from each tribal ethical/research committee. RESULTS: Twenty healthcare providers from varied geographic settings, provider types, and ethnic backgrounds participated in this study. Knowledge regarding contexts surrounding gender in AI/AN communities varied. Long-standing effects of settler colonialism, trauma, and systemic issues presented as overarching concepts. Participants also shared a number of patient and provider-side barriers impacting care and suggested solutions to reduce these barriers. CONCLUSIONS: Patient and provider-side barriers inhibit AI/AN transgender and 2S youth access to healthcare. Historical trauma and community resilience play a role in health for these youth. Understanding history, the intersection of identities, and community strengths can help with the development of solutions to provide high quality care to AI/AN transgender or 2S youth.

Population dynamics of threatened Lahontan cutthroat trout in Summit Lake, Nevada.

Summit Lake, Nevada (USA) is the last high-desert terminal lake to have a native self-sustaining population of threatened Lahontan cutthroat trout (Oncorhynchus clarkii henshawi). From spring 2015 to fall 2017, we quantified adult abundance and survival and the total annual spawning run. Abundance and survival were estimated with mark-recapture using PIT tags, and the annual spawning run was estimated with PIT tag detections and counts of spawners. Adult abundance fluctuated from 830 (95% CI 559-1248) to 1085 (95% CI 747-1614), with no overall temporal trend, as a decrease in male abundance was generally offset by an equal increase in female abundance. Estimated mean adult survival was 0.51 (95% CI 0.44-0.58). The spawning run increased from 645 (2015) to 868 (2016), but then decreased slightly to 824 (2017, mean = 789 ± 118). Female spawners increased in 2016 but decreased slightly in 2017, whereas male spawners decreased each year. In addition, the proportion of adults that spawned each year increased overall. Our study suggests that the adult population remained stable although most of the study period included the recent, severe regional drought in the western United States (2012-2016).

Historical trauma in American Indian/Native Alaska communities: a multilevel framework for exploring impacts on individuals, families, and communities.

Over multiple generations, American Indian communities have endured a succession of traumatic events that have enduring consequences for community members. This article presents a multilevel framework for exploring the impact of historically traumatic events on individuals, families, and communities. The critical connection between historically traumatic events and contemporary stressors is also discussed at length.

Perceptions of child neglect among urban American Indian/Alaska native parents.

A survey of 101 American Indian/Alaska Native (AIAN) parents in Los Angeles was conducted to explore perceptions of child neglect among urban AIAN parents and factors associated with perceptions. Participants rated substance abuse by parents as the most serious type of neglect. Providing material necessities and providing adequate structure were ranked as the least serious types of neglect. Gender, education, marital status, and indirect experience with Child Protective Services were significantly related to perceptions of neglect among urban AIAN parents.

The domestic cat antibody response to feline herpesvirus-1 increases with age.

Herpesviruses establish lifelong infections, normally characterized by prolonged periods of latency with intermittent episodes of viral reactivation. Feline herpesvirus-1 (FHV-1) infects domestic cats, and epidemiological studies indicate that many or most domestic cats are exposed to FHV-1, but the strength and longevity of the antibody response to FHV-1 is not fully characterized. Here we describe development of an ELISA, using lysates of cat cells infected with FHV-1, that measure feline antibodies against FHV-1. The assay is sensitive, quantitative and has a large dynamic range. We found that serum anti-FHV-1 antibodies primarily recognize FHV-1 proteins of the Late (L) class and are primarily of the IgG isotype. We then analyzed serum from a cross-sectional cohort of 100 client-owned cats that differed in age, sex and vaccination history. While there was no difference in FHV-1 antibody responses between females and males, antibody levels were significantly increased in older cats in comparison with younger animals (p=0.01). Surprisingly, as the length of time since the most recent vaccination increased, there was no corresponding drop in serum anti-FHV-1 antibody. These data suggest that FHV-1 immunity is very long-lived and support the current recommendation that many cats do not require revaccination against FHV-1 annually.

Assessment of Risk and Protection in Native American Youth: Steps Toward Conducting Culturally Relevant, Sustainable Prevention in Indian Country.

Background: This study constitutes a building block in the cultural adaptation of Communities That Care (CTC), a community-based prevention system that has been found to be effective in reducing youth problem behaviors. Methods: Using the data from the CTC normative survey dataset that consists of more than quarter million youth nationwide, this study examines the reliability and validity of scores derived from the Communities That Care Youth Survey (CTC-YS), one of the primary assessment tools for gathering community data on risk and protective factors related to problem behaviors including substance use. The reliability and criterion validity analyses are conducted overall for the nationwide sample of youth as well as for the student subsample of Native American youth. Results: The results of this study indicate that the existing CTC-YS assessments of risk and protective factors in the domains of community, family, school, and peer groups as well as within individuals yield scores that are reliable and valid within the Native American sample of youth. Conclusions: This study informs the third step in the CTC prevention planning process, which involves the assessment of risk and protective factors to be targeted in preventive interventions. The question of how the assessment of risk and protective factors among Native American youth might be further improved and a description of efforts related to the cultural adaptation of the CTC program currently underway are also addressed in the discussion.