A role for a Trypanosoma brucei cytosine RNA methyltransferase homolog in ribosomal RNA processing.

In Trypanosoma brucei, gene expression is primarily regulated posttranscriptionally making RNA metabolism critical. T. brucei has an epitranscriptome containing modified RNA bases. Yet, the identity of the enzymes catalyzing modified RNA base addition and the functions of the enzymes and modifications remain unclear. Homology searches indicate the presence of numerous T. brucei cytosine RNA methyltransferase homologs. One such homolog, TbNop2 was studied in detail. TbNop2 contains the six highly conserved motifs found in cytosine RNA methyltransferases and is evolutionarily related to the Nop2 protein family required for rRNA modification and processing. RNAi experiments targeting TbNop2 resulted in reduced levels of TbNop2 RNA and protein, and a cessation of parasite growth. Next generation sequencing of bisulfite-treated RNA (BS-seq) detected the presence of two methylation sites in the large rRNA; yet TbNop2 RNAi did not result in a significant reduction of methylation. However, TbNop2 RNAi resulted in the retention of 28S internal transcribed spacer RNAs, indicating a role for TbNop2 in rRNA processing.

Real-World Evaluation of Primary Versus Secondary Prevention of Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: Anti-osteoclast treatment with denosumab or zoledronate is known to effectively reduce the need for radiotherapy to bone and other skeletal-related events (SREs) in patients with metastatic castration-resistant prostate cancer (mCRPC). In this study, we analyze primary versus secondary initiation of bone-targeting agents (BTAs) relative to first palliative bone radiotherapy in patients dying of mCRPC. METHODS: Provincial administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n = 98 646) who received continuous androgen deprivation therapy (n = 29 453), died of prostate cancer (2013-2018, n = 3864), and received life-prolonging therapy for mCRPC (n = 1850). Variables were collected looking back 3 years from death. Multivariable analysis explored the relationship between clinical variables and BTAs. RESULTS: Of the 58% (1066/1850) patients with mCRPC who received BTA, only 289 (25.4%) started BTA prior to first palliative bone radiotherapy as primary prevention. Eight hundred and forty-eight (74.6%) patients either never received BTA before death (n = 447) or started BTA only after first bone radiotherapy (n = 401). More patients received denosumab (n = 825, 77%) than zoledronic acid (n = 241, 23%). 51.2% (582/1137) of palliative bone radiotherapy was initiated in the last 12 months of life. Factors associated with the use of BTA included elevated alkaline phosphatase (OR = 1.0, P = .023), de novo metastases (OR = 1.4, P = .005), medical oncologist involvement (OR = 2.0, P = .007), diagnosis 2012-2017 versus 2007-2011 (OR = 0.75, P = .034), and academic center (OR = 0.061, P = .007). CONCLUSION: A majority of patients with mCRPC never receive BTAs prior to first SRE, despite universal access and availability of these agents in Ontario. These results highlight an opportunity to improve outcomes by emphasizing early introduction of BTA in patients with mCRPC being started on systemic therapy.

Variation in Access to Palliative Radiotherapy in Prostate Cancer: A Population-Based Study in Canada.

BACKGROUND: As a result of improvements in cancer therapies, patients with metastatic malignancies are living longer, and the role of palliative radiotherapy has become increasingly recognized. However, access to adequate palliative radiotherapy may continue to be a challenge, as is evident from the high proportion of patients dying of prostate cancer who never receive palliative radiotherapy. The main objective of this investigation is to identify and describe the factors associated with the receipt of palliative radiation treatment in a decedent cohort of prostate cancer patients in Ontario. METHODOLOGY:  Population-based administrative databases from Ontario, Canada, were used to identify prostate cancer decedents, 65 years or older who received androgen deprivation therapy between January 1, 2013, and December 31, 2018. Baseline and treatment characteristics were analyzed using univariate and multivariate logistic regression models for association with receipt of radiotherapy in a two-year observation period before death. RESULTS: We identified 3,788 prostate cancer decedents between 2013 and 2018; among these, 49.9% received radiotherapy in the two years preceding death. There were statistically significant positive associations between receipt of radiotherapy and younger age at diagnosis (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.1-2.3); higher stage at diagnosis (OR 1.3, 95% CI 1.1-1.7); receipt of care at a regional cancer center (OR 1.8, 95% CI 1.3-2.4); and involvement of radiation oncologists (OR 155.1, 95% CI 83.3-288.7) or medical oncologists (OR 1.4, 95% CI 1.1-1.8). However, there were no associations between receipt of radiotherapy and income, distance to the nearest cancer center, involvement of urologists in cancer care, healthcare administrative region, home-care involvement, or number of hospitalizations in the observation period. CONCLUSIONS: We found the utilization of palliative radiotherapy for prostate cancer patients in Ontario varies depending on age, stage at diagnosis, number of comorbidities, registration at regional cancer centers, and involvement of oncologists. There were no differences detected based on income or distance from a cancer center. The findings of this study represent an important opportunity to facilitate better access to palliative radiotherapy and referrals to multidisciplinary regional cancer centers, to improve the quality of life of this patient population.

Using reflective practice to support PhD students in the biosciences.

Postgraduate study can be mentally, physically and emotionally challenging. The levels of anxiety and depression in postgraduate students are much higher than those in the general population, and isolation can also be a problem, especially for students who are marginalised due to gender, race, sexuality, disability or being a first-generation and/or international student. These challenges are not new, but awareness of them has increased over the past decade, as have efforts by institutions to make students feel supported. Under the umbrella of a Doctoral Training Partnership, we developed a programme in which reflective practice is employed to help postgraduate students navigate work environments, deal with difficult supervisory or professional relationships, and improve their work-life balance. Additionally, this reflective practice is allowing the training partnership to tailor support to its students, enabling them to effectively nurture our next generation of bioscientists.

Voluntary wheel running mitigates disease in an Orai1 gain-of-function mouse model of tubular aggregate myopathy.

Tubular aggregate myopathy (TAM) is an inherited skeletal muscle disease associated with progressive muscle weakness, cramps, and myalgia. Tubular aggregates (TAs) are regular arrays of highly ordered and densely packed SR straight-tubes in muscle biopsies; the extensive presence of TAs represent a key histopathological hallmark of this disease in TAM patients. TAM is caused by gain-of-function mutations in proteins that coordinate store-operated Ca2+ entry (SOCE): STIM1 Ca2+ sensor proteins in the sarcoplasmic reticulum (SR) and Ca2+-permeable ORAI1 channels in the surface membrane. We have previously shown that voluntary wheel running (VWR) prevents formation of TAs in aging mice. Here, we assessed the therapeutic potential of endurance exercise (in the form of VWR) in mitigating the functional and structural alterations in a knock-in mouse model of TAM (Orai1G100S/+ or GS mice) based on a gain-of-function mutation in the ORAI1 pore. WT and GS mice were singly-housed for six months (from two to eight months of age) with either free-spinning or locked low profile wheels. Six months of VWR exercise significantly increased soleus peak tetanic specific force production, normalized FDB fiber Ca2+ store content, and markedly reduced TAs in EDL muscle from GS mice. Six months of VWR exercise normalized the expression of mitochondrial proteins found to be altered in soleus muscle of sedentary GS mice in conjunction with a signature of increased protein translation and biosynthetic processes. Parallel proteomic analyses of EDL muscles from sedentary WT and GS mice revealed changes in a tight network of pathways involved in formation of supramolecular complexes, which were also normalized following six months of VWR. In summary, sustained voluntary endurance exercise improved slow twitch muscle function, reduced the presence of TAs in fast twitch muscle, and normalized the muscle proteome of GS mice consistent with protective adaptions in proteostasis, mitochondrial structure/function, and formation of supramolecular complexes.

Cryptogenic Hypervirulent Klebsiella pneumoniae Pyogenic Liver Abscess: A Case Report.

BACKGROUND Klebsiella pneumoniae is a gram-negative organism known to cause pyogenic liver abscesses. It is most often caused by one of the hypervirulent strains, which are capable of causing metastatic infection. This occurs most commonly in Asia in patients without hepatobiliary disease; however, it is becoming increasingly recognized in North America. CASE REPORT We report a previously healthy man in his 50s who presented to hospital with 3 weeks of fever, chills, and mild abdominal pain following a minor motor vehicle collision. Ultrasound and computed tomography of his abdomen revealed a large multi-loculated liver abscess. This was drained percutaneously and grew a hypervirulent strain of Klebsiella pneumoniae known to cause metastatic infection. His blood cultures were negative. In addition to percutaneous drainage, he was treated with 8 weeks of antimicrobial therapy. Fortunately, he did not develop evidence of metastatic infection despite the hypervirulent strain. Etiology of the abscess was not clearly identified; however, it was speculated that the motor vehicle collision could have led to its development through gut translocation. CONCLUSIONS Presentation of Klebsiella pneumoniae liver abscesses is often nonspecific, and clinicians must have a high index of suspicion in order to ensure rapid diagnosis and treatment. Delay in diagnosis is associated with increased morbidity and mortality, and thus it is an important entity for clinicians to be aware of, especially as it becomes more prevalent in North American populations. Additionally, it is important that physicians are aware of the hypervirulent strains and screen patients clinically for evidence of metastatic infection.

A population-based study of factors associated with systemic treatment in advanced prostate cancer decedents.

INTRODUCTION: Life-prolonging therapies (LPTs) are rapidly evolving for the treatment of advanced prostate cancer, although factors associated with real-world uptake are not well characterized. METHODS: In this cohort of prostate-cancer decedents, we analyzed factors associated with LPT access. Population-level databases from Ontario, Canada identified patients 65 years or older with prostate cancer receiving androgen deprivation therapy and who died of prostate cancer between 2013 and 2017. Univariate and multivariable analyses assessed the association between baseline characteristics and receipt of LPT in the 2 years prior to death. RESULTS: Of 3575 patients who died of prostate cancer, 40.4% (n = 1443) received LPT, which comprised abiraterone (66.3%), docetaxel (50.3%), enzalutamide (17.2%), radium-223 (10.0%), and/or cabazitaxel (3.5%). Use of LPT increased by year of death (2013: 22.7%, 2014: 31.8%, 2015: 41.8%, 2016: 49.1%, and 2017: 57.9%, p < 0.0001), driven by uptake of all agents except docetaxel. Adjusted odds of use were higher for patients seen at Regional Cancer Centers (OR: 1.8, 95% CI: 1.5-2.1) and who received prior prostate-directed therapy (OR: 1.3, 95% CI: 1.0-1.5), but lower with advanced age (≥85: OR: 0.54, 95% CI:0.39-0.75), increased chronic conditions (≥6: OR: 0.62, 95% CI: 0.43-0.92), and long-term care residency (OR: 0.38, 95% CI: 0.17-0.89). Income, stage at presentation, and distance to the cancer center were not associated with LPT uptake. CONCLUSION: In this cohort of prostate cancer-decedents, real-world uptake of novel prostate cancer therapies occurred at substantially higher rates for patients receiving care at Regional Cancer Centers, reinforcing the potential benefits for treatment access for patients referred to specialist centers.

The Future of Laboratory Chemistry Learning and Teaching Must be Accessible.

This commentary is a call to make the future of chemistry laboratories accessible and inclusive. We draw from research and lived experience to put forward a list of recommendations for laboratory-based teaching. Our authorial team includes undergraduate and postgraduate chemistry students, graduate teaching assistants, teaching-focused and traditional research and teaching academics, and a Diversity Equality Inclusion (DEI/EDI) academic expert. We all have lived experiences of disability, chronic illness, neurodivergence, and other marginalizations related to race, religion, sexuality, or other characteristics. We believe that laboratory-based chemistry learning environments, teaching, assessment, and resources should be accessible to all students and staff.

Consistency of reports of violence from northern Rakhine state in August 2017.

BACKGROUND: In August 2017, Myanmar's Armed Forces, the Tatmadaw, launched an orchestrated attack on hundreds of Rohingya-majority villages in northern Rakhine state. This study seeks to validate the consistency of previous reports of violence against the Rohingya people in the region carried out by the Tatmadaw, Border Guard Police, and Rakhine villagers in the late summer and early fall of 2017. METHODS: Internal validation data is from a three-armed study. Data analyzed in the external triangulation was sourced through a literature review of known, publicly available surveys and interviews. Both sets of data documented instances of violence against the Rohingya people in northern Rakhine state during the late summer and early fall of 2017. Consistency was evaluated across five indicators of violence: arson, presence of mass graves, reports of sexual violence and human injuries, as well as human fatalities, across 611 locales in northern Rakhine state. Further analysis was conducted to measure consistency of reports by locale and across locales by indicator. RESULTS: Overall, an internal validation of 94 hamlets found that 98% of these locales were consistent across at least four of the five indicators (80% + consistency). Arson and reports of human injuries were the most consistent indicators across locales (100% and 99% consistency, respectively) and sexual violence was the least consistent indicator, with 84% of participating locales exhibiting consistent reports of sexual violence between the qualitative and quantitative data. Similarly, an external validation of 57 locations found that 50 of the 57 locations (88%) were consistent across indicators. Arson was the most consistent across sources (96%), whereas source agreement across locations was the least consistent for reports of sexual violence (58%). CONCLUSION: The government of Myanmar has denied involvement in the 2017 attacks on Rohingya communities in northern Rakhine state and purports that reports of the violence and destruction are overstated. However, consistent reporting from multiple sources on the same locales clearly underscores the veracity of the evidence documented, both by investigative groups and as recounted by Rohingya survivors of violence. It is our hope that this cataloging and comparison of available data, along with this study's assessment of its consistency, will aid ongoing accountability efforts.

Autistic women's views and experiences of infant feeding: A systematic review of qualitative evidence.

LAY ABSTRACT: What is already known about the topic?Mothers are encouraged to breastfeed their babies due to known health benefits for both babies and mothers. However, although breastfeeding is 'natural', that does not make it easy and many women experience challenges. Autistic women may face additional barriers to breastfeeding when compared to neurotypical women.What this paper adds?We reviewed all existing evidence on Autistic mothers' infant feeding experiences (22 pieces) and found that although many Autistic women wanted to breastfeed, breastfeeding was difficult for Autistic mothers for three key reasons. First, maternity and infant feeding services were inaccessible and unsupportive to Autistic mothers, meaning they did not receive help when needed. Second, becoming a mother was challenging because of exhaustion, loss of control over routines and a lack of social support. Third, when breastfeeding Autistic mothers experienced sensory challenges, such as 'being touched out', and pain, which could feel unbearable. Despite these difficulties, many Autistic mothers had done a lot of reading about breastfeeding and were determined to breastfeed their babies; some mothers found breastfeeding positive. Infant formula was often viewed as second-best compared to breastmilk, but some mothers found the ritual of preparing bottles of formula to be calming.Implications for practice, research or policyThe findings of this work show that Autistic mothers urgently need better support from health professionals to help meet their breastfeeding goals, including how to remove or reduce the extra barriers being Autistic brings to breastfeeding.

Seeking justice amidst chaos: methods to identify and document individuals implicated in crimes against the Rohingya in August 2017.

BACKGROUND: Documenting perpetrators of human rights violations enables effective prosecution and can help prevent future atrocities. Doing so calls for collecting reliable data using verifiable and transparent methodology. We present methods used to document crimes and identify alleged perpetrators implicated in the 2017 attacks against Rohingya civilians in Myanmar. The findings and lessons-learned have relevance to contemporary crises with widespread atrocities. METHODS: A mixed-methods assessment conducted from May to July 2018 included: (1) cross-sectional quantitative surveys among leaders of affected hamlets in northern Rakhine State, (2) qualitative interviews to record hamlet-level accounts, and (3) clinical evaluations of survivors of violence. Survey respondents who reported violence and destruction in each hamlet were asked to identify perpetrators of those acts, including known role or affiliation. The reported names were reviewed for clarity and divergent spellings, repeated references were aggregated, and the names and roles were analyzed and classified by location and affiliation. RESULTS: 143 individuals were implicated in atrocities committed across three Northern Rakhine townships. Each was independently identified by at least three separate survey respondents as directly committing violence or destruction in their hamlet of origin, or as witnessed while fleeing to Bangladesh. Two-thirds (69%) of identified perpetrators were reported by four or more participants and 47% by five or more. Some form of additional identifying information, was provided for 85% of names. The most common affiliations were: Myanmar army (n = 40), Border Guard Police (n = 32), Village Tract Administrators (n = 17), and extremists (n = 25). CONCLUSIONS: The methodology presented here yielded a unique record of individuals purported to have directly committed acts of violence and destruction in Rakhine State in August 2017, forming the most extensive record of individuals implicated in ground-level perpetration of those crimes. This methodology can play a key role in accountability mechanisms for the Rohingya, and in other settings in which perpetrators are many and documentation of their crimes is difficult. The use of survey methods and standardized data collection amongst affected populations to comprehensively characterize crimes committed and to identify individuals implicated in those crimes can serve as a key tool in documentation and an important component of accountability.

Managing research throughout COVID-19: Lived experiences of supramolecular chemists.

The international Women in Supramolecular Chemistry network believes that taking an area-specific approach effectively supports equality, diversity, and inclusion. Science lacks diversity, and this is intersectional. We share effects of coronavirus disease 2019 (COVID-19) by triangulating findings from an online survey, a collaborative autoethnography, and reflective group research meetings. We show how qualitative research with the community offers insights into challenges and supports individuals, and we demonstrate that research leaders have often taken responsibility for their teams' mental health and well-being at the cost of their own.

Streptococcus agalactiae infective endocarditis in Canada: a multicenter retrospective nested case control analysis.

BACKGROUND: Infective endocarditis (IE) caused by Streptococcus agalactiae (GBS) is increasingly reported and associated with an aggressive course and high mortality rate. Existing literature on GBS IE is limited to case series; we compared the characteristics of patients with GBS IE to patients with GBS bacteremia without IE to identify risk factors for development of IE. METHODS: A nested case-control study in a cohort of adult patients with GBS bacteremia over a 18-year period was conducted across seven centres in three Canadian cities. A chart review identified patients with possible or definite IE (per Modified Duke Criteria) and patients with IE were matched to those without endocarditis in a 1:3 fashion. Multivariate analyses were completed using logistic regression. RESULTS: Of 520 patients with GBS bacteremia, 28 cases of possible or definite IE were identified (5.4%). 68% (19/28) met criteria for definite IE, surgery was performed in 29% (8/28), and the overall in-hospital mortality rate was 29% (8/28). Multivariate analysis demonstrated that IE was associated with injection drug use (OR = 19.6, 95% CI = 3.39-111.11, p = 0.001), prosthetic valve (OR = 11.5, 95% CI = 1.73-76.92, p = 0.011) and lack of identified source of bacteremia (OR = 3.81, 95% CI = 1.24-11.65, p = 0.019). CONCLUSIONS: GBS bacteremia, especially amongst people who inject drugs, those with prosthetic valves, and those with no apparent source of infection, should increase clinical suspicion for IE.

An Area-Specific, International Community-Led Approach to Understanding and Addressing Equality, Diversity, and Inclusion Issues within Supramolecular Chemistry.

Diversity, equality, and inclusion (DEI/EDI) are pressing issues in chemistry and the natural sciences. In this Essay we share how an area-specific approach is "calling in" the community so that it can act to address EDI issues, and support those who are marginalised. Women In Supramolecular Chemistry (WISC) is an international network that aims to support equality, diversity, and inclusion within supramolecular chemistry. WISC has taken a field-specific approach using qualitative research methods with scientists to identify the support that is needed and the problems the supramolecular community needs to address. Herein, we present survey data from the community which highlight the barriers that are faced by those who take career breaks for any reason, a common example is maternity leave, and the importance of mentoring to aid progression post-PhD. In conclusion, we set out an interdisciplinary and creative approach to addressing EDI issues within supramolecular chemistry.

Outcomes and costs of skilled support for people with severe or profound intellectual disability and complex needs.

BACKGROUND: With increasing reductions in funding for social care across many countries, the need to ensure that resources are used to best effect is becoming increasingly important, in particular for those with severe and complex needs. METHODS: In order to explore the outcomes and costs of skilled support for this group of people, quality of life was assessed for 110 people in 35 services in England. Information on costs was also collected. RESULTS: People who received consistently good active support experienced better outcomes in terms of several quality of life domains. Good support did not require significantly more staff time, and there was no evidence of higher total costs for those receiving good support. CONCLUSIONS: The inclusion of active support in government guidance and local commissioning practices related to people with severe intellectual disabilities is likely to improve user outcomes. Observation should be an important element in measuring service quality.