Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens.

Functional genomics approaches can overcome limitations-such as the lack of identification of robust targets and poor clinical efficacy-that hamper cancer drug development. Here we performed genome-scale CRISPR-Cas9 screens in 324 human cancer cell lines from 30 cancer types and developed a data-driven framework to prioritize candidates for cancer therapeutics. We integrated cell fitness effects with genomic biomarkers and target tractability for drug development to systematically prioritize new targets in defined tissues and genotypes. We verified one of our most promising dependencies, the Werner syndrome ATP-dependent helicase, as a synthetic lethal target in tumours from multiple cancer types with microsatellite instability. Our analysis provides a resource of cancer dependencies, generates a framework to prioritize cancer drug targets and suggests specific new targets. The principles described in this study can inform the initial stages of drug development by contributing to a new, diverse and more effective portfolio of cancer drug targets.

Corrigendum: Common genetic variation drives molecular heterogeneity in human iPSCs.

This corrects the article DOI: 10.1038/nature22403.

Common genetic variation drives molecular heterogeneity in human iPSCs.

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.

Employment trajectories and health: cohort differences in English and French women.

BACKGROUND: Policy and social change have increased women's participation in the labour market and their opportunity to combine paid work with family care. We analyse whether a specific combination of employment and domestic duties over the life course are associated with variations in English and French women's health, focusing on two birth cohorts. METHODS: We used sequence analysis to group women in English Longitudinal Study of Ageing and Survey of Health, Ageing and Retirement in Europe, according to their work and family histories. Using ordered logistic regression, we tested for group differences in later self-reported health and depressive symptoms, while controlling for a range of adult socio-economic circumstances. RESULTS: The findings confirm important differences between birth cohorts and countries. French women report a higher risk of poor self-reported health and mental issues than English women. Full-time domestic duties were particularly deleterious for the health of the two younger cohorts, whereas a combination of employment and domestic duties across the life course had a positive association with later-life health. DISCUSSION: Further research is needed to explore the mechanisms linking work and care trajectories to poor health.

A systematic review of physical and psychological health and wellbeing of older women in Sub-Saharan Africa.

BACKGROUND: Sub-Saharan Africa (SSA) has the fastest growing proportion of older adults in the world, the majority of whom are women. Global health agendas, however, continue to deprioritise older women's health issues, including the incidence of and mortality from non-communicable disease (NCDs). This is the first systematic review to address the health, wellbeing and healthcare utilization of older SSA women. METHODS: Studies with primary analysis of health, wellbeing and/or healthcare utilization outcomes for women over the age of 50 from SSA countries were included. Databases searched include EMBASE, Scopus and Psycinfo. FINDINGS: About 26 studies from six SSA countries met inclusion criteria. Studies regarding NCDs predominated (n = 12), followed by healthcare utilization (n = 4), disability (n = 4), wellbeing (n = 2), depression (n = 2) and HIV (n = 2). Every study indicated significantly lower self-rated health and wellbeing, higher rates of depression, hypertension, obesity, disability or weakness for women compared with men. The studies also indicated that older women use healthcare more often, and choose public over private facilities more often. INTERPRETATION: The studies in the review had large, diverse samples. This review demonstrates the need for more gender-specific studies to better understand the unique challenges older women face in managing NCDs in particular.

Variability in individual constriction contributions to third formant values in American English /ɹ/.

Although substantial variability is observed in the articulatory implementation of the constriction gestures involved in /ɹ/ production, studies of articulatory-acoustic relations in /ɹ/ have largely ignored the potential for subtle variation in the implementation of these gestures to affect salient acoustic dimensions. This study examines how variation in the articulation of American English /ɹ/ influences the relative sensitivity of the third formant to variation in palatal, pharyngeal, and labial constriction degree. Simultaneously recorded articulatory and acoustic data from six speakers in the USC-TIMIT corpus was analyzed to determine how variation in the implementation of each constriction across tokens of /ɹ/ relates to variation in third formant values. Results show that third formant values are differentially affected by constriction degree for the different constrictions used to produce /ɹ/. Additionally, interspeaker variation is observed in the relative effect of different constriction gestures on third formant values, most notably in a division between speakers exhibiting relatively equal effects of palatal and pharyngeal constriction degree on F3 and speakers exhibiting a stronger palatal effect. This division among speakers mirrors interspeaker differences in mean constriction length and location, suggesting that individual differences in /ɹ/ production lead to variation in articulatory-acoustic relations.

Unsupervised correction of gene-independent cell responses to CRISPR-Cas9 targeting.

BACKGROUND: Genome editing by CRISPR-Cas9 technology allows large-scale screening of gene essentiality in cancer. A confounding factor when interpreting CRISPR-Cas9 screens is the high false-positive rate in detecting essential genes within copy number amplified regions of the genome. We have developed the computational tool CRISPRcleanR which is capable of identifying and correcting gene-independent responses to CRISPR-Cas9 targeting. CRISPRcleanR uses an unsupervised approach based on the segmentation of single-guide RNA fold change values across the genome, without making any assumption about the copy number status of the targeted genes. RESULTS: Applying our method to existing and newly generated genome-wide essentiality profiles from 15 cancer cell lines, we demonstrate that CRISPRcleanR reduces false positives when calling essential genes, correcting biases within and outside of amplified regions, while maintaining true positive rates. Established cancer dependencies and essentiality signals of amplified cancer driver genes are detectable post-correction. CRISPRcleanR reports sgRNA fold changes and normalised read counts, is therefore compatible with downstream analysis tools, and works with multiple sgRNA libraries. CONCLUSIONS: CRISPRcleanR is a versatile open-source tool for the analysis of CRISPR-Cas9 knockout screens to identify essential genes.

Simultaneous electromagnetic articulography and electroglottography data acquisition of natural speech.

This paper reports on the concurrent use of electroglottography (EGG) and electromagnetic articulography (EMA) in the acquisition of EMA trajectory data for running speech. Static and dynamic intersensor distances, standard deviations, and coefficients of variation associated with inter-sample distances were compared in two conditions: with and without EGG present. Results indicate that measurement discrepancies between the two conditions are within the EMA system's measurement uncertainty. Therefore, potential electromagnetic interference from EGG does not seem to cause differences of practical importance on EMA trajectory behaviors, suggesting that simultaneous EMA and EGG data acquisition is a viable laboratory procedure for speech research.

The aetiology of schizophrenia: what have the Swedish Medical Registers taught us?

OBJECTIVE: To review the last thirty years of studies that, using Swedish population registers, have added to our understanding of the aetiology of schizophrenia SAMPLE INCLUDED/METHODS: A literature search was performed to systematically review all studies that using Swedish Population based registers have investigated the aetiology of schizophrenia. Key authors in the field, predominately from Swedish institutions, were additionally contacted and key journals hand searched, for missing references. A quality assessment methodological review was then conducted on each study. Data was extracted and tabulated on identified aetiological themes RESULTS: 61 articles were included corresponding to 10 identified aetiological themes. Although the majority of included studies were retrospective cohort studies, case control studies were also included where they used population based registers. Confirming previous research, schizophrenia was found to have a multi-factorial aetiological basis with pregnancy and birth factors, parental age, social adversity, genetics, substance misuse, migration and ethnicity, personality, non-psychiatric co-morbidity, psychiatric history and poor cognitive performance all found to be significantly associated with an increased risk of later schizophrenia. CONCLUSIONS: Although some difficulties exist in analysing the interplay between each of these factors, the Swedish population registers have added considerably to our understanding of each of the presented individual aetiological themes. The ability to study the whole population over several decades has been particularly useful in determining the timing of exposures.

Community-based person-centred integrated care (PIC) networks for healthy ageing in place: a scoping review protocol.

INTRODUCTION: The economic case for preventive care delivered in or near citizens' homes is strong, and there is growing evidence of the role of local-level support in supporting people's health and well-being as they age. However, effective and consistent delivery of person-centred integrated care (PIC) at the community level remains elusive. Previous systematic reviews have focused on specific processes such as case management, but none have focused on the operational delivery of community-based care networks. In this study, we aim to identify what practice-based models of PIC networks exist at the local/neighbourhood level and what evidence is available as to their effectiveness for healthy ageing in place. METHODS AND ANALYSIS: We will undertake a scoping review following the framework proposed by Arksey and O'Malley and updated guidance by the Joanna Briggs Institute. Peer-reviewed sources will be identified through searches of seven databases, and relevant grey literature will be identified through websites of policy and voluntary sector organisations focused on integrated care and/or healthy ageing. Data from included studies will be extracted for relevance to the research questions, including aims and anticipated outcomes of network models, financial and management structures of networks, and evidence of evaluation. Summary tables and narrative comparisons of key PIC network features across settings will be presented. ETHICS AND DISSEMINATION: As no primary data will be collected, ethical approval is not required to conduct this scoping review. In addition to publication as a peer-reviewed article, the results of this review will be summarised as shorter discussion papers for use in follow-up research.

Functional Transitions Among Older Adults in Rural China: Examining the Differential Roles of Care From Daughters' and Sons' Families.

OBJECTIVES: Informal care provided by adult children is of great importance for older adults' well-being in China. This paper investigates and compares the functional transitions among older adults living in rural areas who receive care from daughters' and from sons' families. METHODS: This study utilizes the "Well-being of Elderly Survey in Anhui Province" (WESAP) from 2001 to 2021. Our sample included 2,797 individuals aged 60 years or older. Functional status was based on the activities of daily living and the instrumental activities of daily living. We employed a random-effects ordered logit model to examine the functional transitions among the older adults. RESULTS: Receiving care from daughters' families is significantly associated with a lower likelihood of functional decline compared to receiving care from sons' families in rural China. The advantage associated with daughter care becomes more pronounced among older individuals with a severe functional difficulty compared to those with a mild or moderate functional difficulty. The difference is prevalent among older adults aged 75 and older, with less wealth or multiple chronic diseases, or who live alone. Furthermore, among those with severe functional difficulties, the daughter advantage is more significant for fathers as compared to mothers. DISCUSSION: Nowadays, daughters' families can provide high-quality informal care, often surpassing that offered by sons' families. This daughter advantage becomes even more significant among older adults who have a higher need for family care, such as those with severe disabilities and limited financial resources.

Are all fibrinogen concentrates the same? The effects of two fibrinogen therapies in an afibrinogenemic patient and in a fibrinogen deficient plasma model. A clinical and laboratory case report.

The choice of treatments for inherited, or acquired, fibrinogen deficient states is expanding and there are now several fibrinogen concentrate therapies commercially available. Patients with the rare inherited bleeding disorder, afibrinogenemia, commonly require life-long replacement therapy with fibrinogen concentrate to prevent hemorrhagic complications. Recent reports in the setting of acquired bleeding, namely trauma hemorrhage, have highlighted the potential importance of the different compositions of fibrinogen supplements, including cryoprecipitate and the various plasma- derived concentrates. Clot strength and the subsequent susceptibility of a clot to lysis is highly dependent on the amount of fibrinogen as well as its structural composition, the concentration of pro- and anti-coagulant factors, as well as fibrinolytic regulators, such as factor XIII (FXIII). This report details the effects of two commercially available fibrinogen concentrates (Riastap®, CSL Behring and Fibryga®, Octapharma) on important functional measures of clot formation and lysis in a patient with afibrinogenemia. Our report offers insights into the differential effects of these concentrates, at the clot level, according to the variable constituents of each product, thereby emphasizing that the choice of fibrinogen concentrate can influence the stability of a clot in vivo. Whether this alters clinical efficacy is yet to be understood.

Fishing for subsistence constitutes a livelihood safety net for populations dependent on aquatic foods around the world.

Fishing for subsistence constitutes a livelihood safety net for poverty, malnutrition and gender inequality for populations dependent upon aquatic foods around the world. Here we provide global estimates showing that almost the same amount of small-scale fishers engage in subsistence fishing at some point during the year as in commercial employment and use subsistence estimates to measure small-scale fisheries' livelihood safety net function. In 2016, we estimate that 52.8 million people were engaged in subsistence fishing at some point during the year, while another 60.2 million people were commercially employed (90% of global fisheries employment). From 14 country case studies, it was possible to estimate that the subsistence catch provided an average apparent intake of six nutrients critical for positive health outcomes, equivalent to 26% of the recommended daily nutrient intake for 112.5 million people, higher than the national average contribution of beef or poultry.

Researchers' responsibility to uphold Indigenous rights.

Too often research brings harm to Indigenous peoples.

Feasibility and Usability of a Mobile App-Based Interactive Care Plan for Migraine in a Community Neurology Practice: Development and Pilot Implementation Study.

BACKGROUND: Migraine is a common and major cause of disability, poor quality of life, and high health care use. Access to evidence-based migraine care is limited and projected to worsen. Novel mobile health app-based tools may effectively deliver migraine patient education to support self-management, facilitate remote monitoring and treatment, and improve access to care. The risk that such an intervention may increase the care team workload is a potential implementation barrier. OBJECTIVE: This study aims to describe a novel electronic health record-integrated mobile app-based Migraine Interactive Care Plan (MICP) and evaluate its feasibility, usability, and impact on care teams in a community neurology practice. METHODS: Consecutive enrollees between September 1, 2020, and February 16, 2022, were assessed in a single-arm observational study of usability, defined by 74.3% (127/171) completing ≥1 assigned task. Task response rates, rate and type of care team escalations, and patient-reported outcomes were summarized. Patients were prospectively recruited and randomly assigned to routine care with or without the MICP from September 1, 2020, to September 1, 2021. Feasibility was defined by equal to or fewer downstream face-to-face visits, telephone contacts, and electronic messages in the MICP cohort. The Wilcoxon rank-sum test was used to compare continuous variables, and the chi-square test was used for categorical variables for those with at least 3 months of follow-up. RESULTS: A total of 171 patients were enrolled, and of these, 127 (74.3%) patients completed ≥1 MICP-assigned task. Mean escalations per patient per month was 0.9 (SD 0.37; range 0-1.7). Patient-confirmed understanding of the educational materials ranged from 26.6% (45/169) to 56.2% (95/169). Initial mean headache days per week was 4.54 (SD 2.06) days and declined to 2.86 (SD 1.87) days at week 26. The percentage of patients reporting favorable satisfaction increased from a baseline of 35% (20/57) to 83% (15/18; response rate of 42/136, 30.9% to 28/68, 41%) over the first 6 months. A total of 121 patients with MICP were compared with 62 patients in the control group. No differences were observed in the rate of telephone contacts or electronic messages. Fewer face-to-face visits were observed in the MICP cohort (13/121, 10.7%) compared with controls (26/62, 42%; P<.001). CONCLUSIONS: We describe the successful implementation of an electronic health record-integrated mobile app-based care plan for migraine in a community neurology practice. We observed fewer downstream face-to-face visits without increasing telephone calls, medication refills, or electronic messages. Our findings suggest that the MICP has the potential to improve patient access without increasing care team workload and the need for patient input from diverse populations to improve and sustain patient engagement. Additional studies are needed to assess its impact in primary care.

Apraxia of speech with phonological alexia and agraphia following resection of the left middle precentral gyrus: illustrative case.

BACKGROUND: Apraxia of speech is a disorder of speech-motor planning in which articulation is effortful and error-prone despite normal strength of the articulators. Phonological alexia and agraphia are disorders of reading and writing disproportionately affecting unfamiliar words. These disorders are almost always accompanied by aphasia. OBSERVATIONS: A 36-year-old woman underwent resection of a grade IV astrocytoma based in the left middle precentral gyrus, including a cortical site associated with speech arrest during electrocortical stimulation mapping. Following surgery, she exhibited moderate apraxia of speech and difficulty with reading and spelling, both of which improved but persisted 6 months after surgery. A battery of speech and language assessments was administered, revealing preserved comprehension, naming, cognition, and orofacial praxis, with largely isolated deficits in speech-motor planning and the spelling and reading of nonwords. LESSONS: This case describes a specific constellation of speech-motor and written language symptoms-apraxia of speech, phonological agraphia, and phonological alexia in the absence of aphasia-which the authors theorize may be attributable to disruption of a single process of "motor-phonological sequencing." The middle precentral gyrus may play an important role in the planning of motorically complex phonological sequences for production, independent of output modality.

The impact of son or daughter care on Chinese older adults' mental health.

RATIONALE: The traditional cultural norm in China is that eldercare should be offered by a son and his family. However, several decades of family planning policies and rapid economic growth have led to low fertility rates, urbanisation, and cultural change, resulting in both reduced household size and the availability of sons. The traditional eldercare system is thus being challenged, especially in urban areas, with an increasing number of daughters supporting their parents, enabled by rising female empowerment, formal economic employment and improved financial capacities. Existing studies examine and compare the amount and types of support provided by sons and daughters, but very little is known about the differential health outcomes of parents experiencing eldercare offered by sons and by daughters. OBJECTIVE: This study investigates the difference in mental health outcomes of parents who receive eldercare from their sons and from their daughters. METHOD: We analyse waves 2013, 2015, and 2018 of the China Health and Retirement Longitudinal Study, with mental health measured by a 10-item Center for Epidemiological Studies-Depression (CES-D-10) score. We compare the CES-D-10 score between parents with different sources of care - son's family, daughter's family or other - with multivariate statistical analysis. RESULTS: Receiving regular care from a son (or a daughter-in-law) is associated with a lower CES-D score than from a daughter (or a son-in-law). The difference mainly exists amongst those with a stronger son preference and those who are heavily deponent on their children, in particular rural parents, mothers, and those with less wealth. CONCLUSION: Our study explores the evidence on mental health inequalities among parents with different sources of care, highlighting that lack of son care creates an apparent mental health disadvantage. Lowering older adults' dependency on their children may alleviate this inequality by improving their financial independence. We also suggest the development of a long-term care system and greater facilitation of older adults to take-up supplementary services for family care.

Pregnancy and the Singing Voice: A Survey of What Singers Report.

Pregnancy has profound effects on a variety of body systems by way of hormonal and physical changes. Many of these changes directly affect body systems involved in singing. Assumptions exist about what can happen to a person's voice during pregnancy, but these assumptions are based on theoretical predictions leaving little knowledge of the lived experiences of voice changes during pregnancy. An anonymous mixed-method survey was given to 321 professional singers to gain insights on the lived experiences of pregnant singers. This investigation explored what people were told about the effects of pregnancy on the voice in comparison to what they actually experienced. Results show that about half of the respondents' experience matched what they were told for respiration. For phonation and vocal quality less than 25% respondent's experience matched what they were told. In addition, most of the information respondents received came from friends, colleagues, and teachers compared to medical professionals suggesting a need for more interdisciplinary education to best prepare vocalists who are contemplating becoming pregnant.

Development and acceptability of a mobile health application integrated with the electronic heath record for treatment of chronic insomnia disorder.

STUDY OBJECTIVES: To describe the development and feasibility of a cognitive behavioral therapy for insomnia (CBT-I) program delivered via personal digital devices and fully integrated with the electronic health record (EHR). METHODS: A multidisciplinary team of clinicians and members of our Center for Digital Health collaborated to develop a Chronic Insomnia Interactive Care Plan (ChI-ICP), an application that provides personalized and just in time education and promotes self-management using CBT-I concepts, and is activated from and fully integrated into the EHR. Following development, we evaluated patient engagement and workflows, assessed changes to provider workload, and examined outcomes on measures of insomnia during a pilot deployment of the application. RESULTS: A total of 222 patients were enrolled and 179 engaged with the plan during the 3-month pilot program. Enrolled patients generated an average of 3.9 ± 2.3 In Basket messages, most being automated notifications related to noncompletion of assigned tasks, while only a few were related to patients requesting additional training or help with insomnia. Sleep efficiency improved from baseline until the completion of the program from 74.5% ± 16.7% to 87.6% ± 10.8% (P = .001), and the Insomnia Severity Index improved from 14.9 ± 5.22 to 11.6 ± 4.80 (P = .006). CONCLUSIONS: In this pilot implementation of an integrated ChI-ICP, patient engagement was favorable, workflows and workload were not significantly burdensome for the care teams, and initial evaluation of efficacy was favorable. This provides evidence for an application that is a scalable method to assist patients with chronic insomnia and future work should assess its efficacy in controlled trials. CITATION: Morgenthaler TI, Kolla BP, Anderson SE, et al. Development and acceptability of a mobile health application integrated with the electronic heath record for treatment of chronic insomnia disorder. J Clin Sleep Med. 2022;18(12):2785-2792.