Newborn Hearing Screening Results for Infants With Prenatal Opioid Exposure in Southern Appalachia.

PURPOSE: Infants prenatally exposed to opioids exhibit withdrawal symptomology that introduce physiological noise and can impact newborn hearing screening results. This study compared the referral rate and physiological noise interpreted by number of trials rejected due to artifact on initial newborn hearing screenings of infants with prenatal opioid exposure (POE) and infants with no opioid exposure (NOE). Furthermore, within the POE group, it examined the relationship of referral rates with severity of withdrawal symptomology, and with maternal and infant risk factors. METHOD: This study used a retrospective cohort design of electronic medical records from six delivery hospitals in South-Central Appalachia. Newborn hearing screenings were conducted using automated auditory brainstem response (ABR) for 334 infants with POE and 226 infants with NOE. Severity of withdrawal symptomology was measured using the Modified Finnegan Neonatal Abstinence Scoring Tool, which includes observation of behaviors that introduce physiological noise. RESULTS: There was no significant difference in newborn hearing screening referral rate between infants with POE and infants with NOE. Referral rate was not affected by maternal or infant risk factors. Infants with POE had statistically significant higher artifact (defined as rejected ABR sweeps) than infants with NOE. There was a strong positive correlation between Finnegan scores and artifact but not referral rates. Sensitivity and specificity analysis indicated artifact decreased substantially after Day 4 of life. CONCLUSIONS: Referral rates of infants with POE were similar to those of infants with NOE. Nevertheless, the withdrawal symptomology of infants with POE introduces physiological noise reflected as artifact on ABR, which can affect efficiency of newborn hearing screenings.

SIOP pediatric oncology services Global Mapping Program: Latin American data collection.

The International Society of Paediatric Oncology (SIOP) launched a program to map all pediatric cancer facilities around the world. After the results in Africa were completed, the strategy for data collection for Latin America was revised to improve the accuracy and avoid duplications. In partnership with SIOP, the Sociedad Latino Americana de Oncología Pediátrica (SLAOP) approached their delegates who provided the contacts for a 10-question survey about their institutional capacities. Data were collected by email, online meetings, or telephone calls, and stored in a secure platform. All but one country participated and a high number of centers were recorded.

Access to Methotrexate Monitoring in Latin America: A Multicountry Survey of Supportive Care Capacity.

High-dose methotrexate (HDMTX) is used to treat a broad spectrum of cancers. Methotrexate (MTX) monitoring and adequate supportive care are critical for safe drug administration; however, MTX level timing is not always possible in low- and middle-income countries. The aim of this study was to evaluate HDMTX supportive care capacity and MTX monitoring practices in Latin America (LATAM) to identify gaps and opportunities for improvement. A multicenter survey was conducted among LATAM pediatric oncologists. Twenty healthcare providers from 20 institutions answered the online questionnaire. HDMTX was used to treat acute lymphoblastic leukemia (ALL; 100%), non-Hodgkin lymphoma (84.2%), diffuse large B-cell lymphoma (47.4%), osteosarcoma (78.9%), and medulloblastoma (31.6%). Delays in starting HDMTX infusion were related to bed shortages (47.4%) and MTX shortages (21.1%). MTX monitoring was performed at an in-hospital laboratory in 52%, at an external/nearby laboratory in 31.6%, and was not available in 10.5%. Median interval between sampling and obtaining MTX levels was ≤ 2 h in 45% and ≥ 6 h in 30%, related to laboratory location. Sites without access to MTX monitoring reduced the MTX dose for patients with high-risk ALL or did not include MTX in the treatment of patients with osteosarcoma. Respondents reported that implementation of point-of-care testing of MTX levels is feasible. In LATAM, highly variable supportive care capacity may affect the safe administration of MTX doses. Improving accessibility of MTX monitoring and the speed of obtaining results should be prioritized to allow delivery of full doses of MTX required by the current protocols.

The contributions of rare inherited and polygenic risk to ASD in multiplex families.

Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having two or more autistic children. Using this study design, we identify seven previously unrecognized ASD risk genes supported by a majority of rare inherited variants, finding support for a total of 74 genes in our cohort and a total of 152 genes after combined analysis with other studies. Autistic children from multiplex families demonstrate an increased burden of rare inherited protein-truncating variants in known ASD risk genes. We also find that ASD polygenic score (PGS) is overtransmitted from nonautistic parents to autistic children who also harbor rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD PGS overtransmission. These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD.

Prospects for Leveling the Playing Field for Black Children With Autism.

Among the many race-based health disparities that have persistently plagued the US population,1 the disproportionate burden of adverse neurodevelopmental outcomes to Black children affected by autism spectrum disorder (ASD) is particularly devastating given its major lifelong consequences. Recently, in 3 successive reports from the Autism and Developmental Disabilities Monitoring (ADDM) program of the US Centers for Disease Control and Prevention (CDC) (birth cohort years 2014, 2016, and 2018), we and our collaborators reported that although the prevalence of community-diagnosed ASD had equalized for Black and non-Hispanic White (NHW) children in the United States, there has persisted a pronounced racial disparity in the proportion of ASD-affected children with comorbid intellectual disability (ID), on the order of 50% for Black children with ASD vs 20% for White children with ASD.2 Here, we provide data to support the following: much earlier diagnosis is possible; early diagnosis alone is not likely to close the ID comorbidity disparity; and judicious efforts over care as usual are necessary to ensure that Black children have access to timely implementation of developmental therapy, for which we observed promising associations with improved cognitive and adaptive outcomes in our sample.

The Triad Na+ Activated Na+ Channel (Nax)-Salt Inducible KINASE (SIK) and (Na+ + K+)-ATPase: Targeting the Villains to Treat Salt Resistant and Sensitive Hypertension.

The Na+-activated Na+ channel (Nax) and salt-inducible kinase (SIK) are stimulated by increases in local Na+ concentration, affecting (Na+ + K+)-ATPase activity. To test the hypothesis that the triad Nax/SIK/(Na+ + K+)-ATPase contributes to kidney injury and salt-sensitive hypertension (HTN), uninephrectomized male Wistar rats (200 g; n = 20) were randomly divided into 4 groups based on a salt diet (normal salt diet; NSD-0.5% NaCl-or high-salt diet; HSD-4% NaCl) and subcutaneous administration of saline (0.9% NaCl) or deoxycorticosterone acetate (DOCA, 8 mg/kg), as follows: Control (CTRL), CTRL-Salt, DOCA, and DOCA-Salt, respectively. After 28 days, the following were measured: kidney function, blood pressure, (Na+ + K+)-ATPase and SIK1 kidney activities, and Nax and SIK1 renal expression levels. SIK isoforms in kidneys of CTRL rats were present in the glomerulus and tubular epithelia; they were not altered by HSD and/or HTN. CTRL-Salt rats remained normotensive but presented slight kidney function decay. HSD rats displayed augmentation of the Nax/SIK/(Na+ + K+)-ATPase pathway. HTN, kidney injury, and kidney function decay were present in all DOCA rats; these were aggravated by HSD. DOCA rats presented unaltered (Na+ + K+)-ATPase activity, diminished total SIK activity, and augmented SIK1 and Nax content in the kidney cortex. DOCA-Salt rats expressed SIK1 activity and downregulation in (Na+ + K+)-ATPase activity in the kidney cortex despite augmented Nax content. The data of this study indicate that the (Na+ + K+)-ATPase activity response to SIK is attenuated in rats under HSD, independent of HTN, as a mechanism contributing to kidney injury and salt-sensitive HTN.

A Systematic Review of High-Dose Methotrexate for Adults with Primary Central Nervous System Lymphoma.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma that is confined within the CNS. Due to its ability to cross the blood-brain barrier, high-dose methotrexate (HDMTX) is the backbone for induction chemotherapy. This systematic review was conducted to observe outcomes among different HDMTX doses (low, <3 g/m2; intermediate, 3-4.9 g/m2; high, ≥5 g/m2) and regimens used in the treatment of PCNSL. A PubMed search resulted in 26 articles reporting clinical trials using HDMTX for PCNSL, from which 35 treatment cohorts were identified for analysis. The median dose of HDMTX used for induction was 3.5 g/m2 (interquartile range IQR, 3-3.5); the intermediate dose was most frequently used in the studies examined (24 cohorts, 69%). Five cohorts used HDMTX monotherapy, 19 cohorts used HDMTX + polychemotherapy, and 11 cohorts used HDMTX + rituximab ± polychemotherapy. Pooled overall response rate (ORR) estimates for low, intermediate, and high dose HDMTX cohorts were 71%, 76%, and 76%, respectively. Pooled 2-year progression-free survival (PFS) estimates for low, intermediate, and high HDMTX dose cohorts were 50%, 51%, and 55%, respectively. Regimens that included rituximab showed a tendency to have higher ORR and 2-year PFS than those that did not include rituximab. These findings indicate that current protocols utilizing 3-4 g/m2 of HDMTX in combination with rituximab provide therapeutic efficacy in PCNSL.

Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing.

AIMS: High-dose methotrexate (HDMTX) is an essential part of the treatment of several adult and paediatric malignancies. Despite meticulous supportive care during HDMTX administration, severe toxicities, including acute kidney injury (AKI), may occur contributing to patient morbidity. Population pharmacokinetics provide a powerful tool to predict time to clear HDMTX and adjust subsequent doses. We sought to develop and validate pharmacokinetic models for HDMTX in adults with diverse malignancies and to relate systemic exposure with the occurrence of severe toxicity. METHODS: Anonymized, de-identified data were provided from 101 US oncology practices that participate in the Guardian Research Network, a non-profit clinical research consortium. Modelled variables included clinical, laboratory, demographic and pharmacological data. Population pharmacokinetic analysis was performed by means of nonlinear mixed effects modelling using MonolixSuite. RESULTS: A total of 693 HDMTX courses from 243 adults were analysed, of which 62 courses (8.8%) were associated with stage 2/3 acute kidney injury (43 stage 2, 19 stage 3). A three-compartment model adequately fitted the data. Time-dependent serum creatinine, baseline serum albumin and allometrically scaled bodyweight were clinically significant covariates related to methotrexate clearance. External evaluation confirmed a satisfactory predictive performance of the model in adults receiving HDMTX. Dose-normalized methotrexate concentration at 24 and 48 hours correlated with AKI incidence. CONCLUSION: We developed a population pharmacometric model that considers weight, albumin and time-dependent creatinine that can be used to guide supportive care in adult patients with delayed HDMTX elimination.

What Is Autistic Burnout? A Thematic Analysis of Posts on Two Online Platforms.

Background: Compared with adults in the general population, autistic adults are more likely to experience poor mental health, which can contribute to increased suicidality. While the autistic community has long identified autistic burnout as a significant mental health risk, to date, only one study has been published. Early research has highlighted the harmful impact of autistic burnout among autistic adults and the urgent need to better understand this phenomenon. Methods: To understand the lived experiences of autistic adults, we used data scraping to extract public posts about autistic burnout from 2 online platforms shared between 2005 and 2019, which yielded 1127 posts. Using reflexive thematic analysis and an inductive "bottom-up" approach, we sought to understand the etiology, symptoms, and impact of autistic burnout, as well as prevention and recovery strategies. Two autistic researchers with self-reported experience of autistic burnout reviewed the themes and provided insight and feedback. Results: We identified eight primary themes and three subthemes across the data. (1) Systemic, pervasive lack of autism awareness. (1.1) Discrimination and stigma. (2) A chronic or recurrent condition. (3) Direct impact on health and well-being. (4) A life unlived. (5) A blessing in disguise? (6) Self-awareness and personal control influence risk. (6.1) "You need enough balloons to manage the weight of the rocks." (7) Masking: Damned if you do, damned if you don't. (8) Ask the experts. (8.1) Stronger together. The overarching theme was that a pervasive lack of awareness and stigma about autism underlie autistic burnout. Conclusions: We identified a set of distinct yet interrelated factors that characterize autistic burnout as a recurring condition that can, directly and indirectly, impact autistic people's functioning, mental health, quality of life, and well-being. The findings suggest that increased awareness and acceptance of autism could be key to burnout prevention and recovery.

What was the purpose of this study?: Although the autistic community has talked about autistic burnout for a long time, there has not been much research about the topic. This study aimed to investigate autistic burnout from the perspective of autistic adults to understand what they think causes it, the symptoms and impact on their lives, and what can be done to assist prevention and recovery. Why is this an important issue?: This issue is important because autistic people have said that autistic burnout can severely affect their quality of life and well-being and contribute to poor mental health, including the risk of suicide. What did the researchers do?: We used a computer program to collect public posts from two online platforms to look at how autistic adults described autistic burnout. We collected 1127 posts shared over a 12-year period by 683 users. To understand the adults' lived experiences, we analyzed their language at the surface level and looked for common themes across the data. What were the results of the study?: The adults in this study said that autistic burnout was often first experienced during adolescence, lasted months or years, and was hard to recover from. They described severe direct and indirect consequences for their physical and mental health, capacity to function, and ability to achieve personal goals. They described a general lack of knowledge about autism, especially among health care professionals, which led to misdiagnosis and inadequate or inappropriate treatment. Masking or "camouflaging" to pass as nonautistic was the most common reason participants gave for autistic burnout. Many used strategies to manage energy levels to avoid burnout. The autistic community was an essential source of information and support for participants. Overall, stigma, discrimination, and low awareness and acceptance of autism were responsible for the cycle of autistic burnout. How do these findings add to what was already known?: As one of the first studies about autistic burnout, we learned that it happens because of factors associated with being autistic and poor autism awareness and acceptance within society. We now know that autistic people often first experience autistic burnout when they are young, but it usually recurs, which can stop autistic people leading fulfilling lives. We learned that difficulty identifying emotions may be a risk factor and that online communication may help autistic people during recovery. We found that some positive consequences of autistic burnout include autism diagnosis in adulthood, finding the autistic community, and making empowering lifestyle changes. What are the potential weaknesses in the study?: We had limited demographic information, so we do not know how diverse the sample was or how factors such as gender, age, race, or identifying as LGBTQI may have influenced some people's experience of autistic burnout. The adults in this study had access to online platforms and could communicate in writing, and so, people with higher communication support needs may not have been included. How will these recommendations help autistic adults now or in the future?: The findings reinforce the personal stories of autistic people and show that autistic burnout is a common, consistent, and harmful experience. The findings show it is vital for health professionals to recognize autistic burnout to provide appropriate care and support because prevention and early detection could help stop the harmful cycle of autistic burnout. The findings underscore the importance of reducing discrimination and stigma against autistic people and increased acceptance.

Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

The Evolving Landscape: Funerals, Cemeteries, Memorialization, and Bereavement Support.

The aim of this study was to provide a better understanding of current memorialization practices and their influence on grief due to bereavement and to explore ways of improving bereavement outcomes. The qualitative research design incorporated two phases, a scoping literature review, followed by in-depth interviews with eight service providers from the funeral, cemetery, and crematorium industries across Australia. The trend toward informal memorialization practices blurs the roles of community members and formal industry service providers. A public health approach to bereavement support that encompasses both groups is recommended as the most appropriate response to the evolving landscape. This approach focuses on building partnerships between industry service providers and other community organizations involved in end-of-life issues. We propose that reframing the role of formal industry service providers as educators and facilitators partnered within compassionate communities will support improved outcomes for the bereaved.

Memorialization Practices Are Changing: An Industry Perspective on Improving Service Outcomes for the Bereaved.

Although considerable research efforts have focused on bereavement outcomes following loss, there are few studies which address the role of memorialization, particularly as it relates to formal service provision. Currently the funeral, cemetery, and crematorium industries are observing a steady decline in traditional and formal memorialization practices. This study aims to identify current memorialization practices and emerging trends, highlight key priorities for improving service outcomes for the bereaved, and understand the implications of changing consumer preferences for service provision. The study's qualitative research design incorporates two phases, a scoping literature review followed by in-depth interviews with eight service providers from the funeral, cemetery, and crematorium industries. A key finding is that the trend toward contemporary and informal memorialization practices blurs the lines between the role of consumers and service providers. There is a clear opportunity for service providers to engage in community education as a means of building supportive relationships with and improving service outcomes for the bereaved.

Access to care for childhood cancers in India: perspectives of health care providers and the implications for universal health coverage.

BACKGROUND: There are multiple barriers impeding access to childhood cancer care in the Indian health system. Understanding what the barriers are, how various stakeholders perceive these barriers and what influences their perceptions are essential in improving access to care, thereby contributing towards achieving Universal Health Coverage (UHC). This study aims to explore the challenges for accessing childhood cancer care through health care provider perspectives in India. METHODS: This study was conducted in 7 tertiary cancer hospitals (3 public, 3 private and 1 charitable trust hospital) across Delhi and Hyderabad. We recruited 27 healthcare providers involved in childhood cancer care. Semi-structured interviews were audio recorded after obtaining informed consent. A thematic and inductive approach to content analysis was conducted and organised using NVivo 11 software. RESULTS: Participants described a constellation of interconnected barriers to accessing care such as insufficient infrastructure and supportive care, patient knowledge and awareness, sociocultural beliefs, and weak referral pathways. However, these barriers were reflected upon differently based on participant perception through three key influences: 1) the type of hospital setting: public hospitals constituted more barriers such as patient navigation issues and inadequate health workforce, whereas charitable trust and private hospitals were better equipped to provide services. 2) the participant's cadre: the nature of the participant's role meant a different degree of exposure to the challenges families faced, where for example, social workers provided more in-depth accounts of barriers from their day-to-day interactions with families, compared to oncologists. 3) individual perceptions within cadres: regardless of the hospital setting or cadre, participants expressed individual varied opinions of barriers such as acceptance of delay and recognition of stakeholder accountabilities, where governance was a major issue. These influences alluded to not only tangible and structural barriers but also intangible barriers which are part of service provision and stakeholder relationships. CONCLUSION: Although participants acknowledged that accessing childhood cancer care in India is limited by several barriers, perceptions of these barriers varied. Our findings illustrate that health care provider perceptions are shaped by their experiences, interests and standpoints, which are useful towards informing policy for childhood cancers within UHC.

Timing of the Diagnosis of Autism in African American Children.

OBJECTIVES: African American (AA) children affected by autism spectrum disorder (ASD) experience delays in diagnosis and obstacles to service access, as well as a disproportionate burden of intellectual disability (ID) as documented in surveillance data recently published by the US Centers for Disease Control and Prevention. Our objective in this study was to analyze data from the largest-available repository of diagnostic and phenotypic information on AA children with ASD, and to explore the wide variation in outcome within the cohort as a function of sociodemographic risk and specific obstacles to service access for the purpose of informing a national approach to resolution of these disparities. METHODS: Parents of 584 AA children with autism consecutively enrolled in the Autism Genetic Resource Exchange across 4 US data collection sites completed event history calendar interviews of the diagnostic odysseys for their children with ASD. These data were examined in relation to developmental outcomes of the children with autism and their unaffected siblings. RESULTS: The average age of ASD diagnosis was 64.9 months (±49.6), on average 42.3 months (±45.1) after parents' first concerns about their children's development. The relationship between timing of diagnosis and ASD severity was complex, and ID comorbidity was not predicted in a straightforward manner by familial factors associated with cognitive variation in the general population. CONCLUSIONS: These findings document significant opportunity to expedite diagnosis, the need to further understand causes of ID comorbidity, and the necessity to identify effective approaches to the resolution of disparities in severity-of-outcome for AA children with autism.

Evaluation of a Pharmacist Led Oral Chemotherapy Clinic: A Pilot Program in the Gastrointestinal Oncology Clinic at an Academic Medical Center.

Oral chemotherapy represents a major patient-centric advancement in therapy convenience. However, ownership of safe and correct administration of these agents requires significant patient education. To address this challenge, an in-person pharmacist-led oral chemotherapy education clinic in gastrointestinal oncology patients within an academic medical center was created and assessed. In this pilot program, a medication-specific quiz was administered to patients before and after education performed by a pharmacist to assess patient understanding of their new oral chemotherapy. A five-question satisfaction survey was also administered at the conclusion of the pharmacist clinic visit. Primary outcome was the percentage difference between pre-and post-education quiz scores. Secondary outcomes included patient satisfaction, time to treatment initiation, and number of pharmacist interventions. Frequencies and medians were used to describe categorical and continuous variables, respectively. Of the 18 patients analyzed, 50% were male and median age was 59.5 years. Approximately 28% had colon cancer, and 61% were treated with capecitabine. The median post-education scores improved from a pre-education score of 75% to 100%. Overall, seventeen of the eighteen patients responded with "strongly agree" to all satisfaction survey statements. An in-person oncology pharmacist-led oral chemotherapy education session demonstrated an improvement in patients' understanding of their new oral chemotherapy treatment.

Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity.

Autism spectrum disorder (ASD) is more prevalent in males than in females, but the neurobiological mechanisms that give rise to this sex-bias are poorly understood. The female protective hypothesis suggests that the manifestation of ASD in females requires higher cumulative genetic and environmental risk relative to males. Here, we test this hypothesis by assessing the additive impact of several ASD-associated OXTR variants on reward network resting-state functional connectivity in males and females with and without ASD, and explore how genotype, sex, and diagnosis relate to heterogeneity in neuroendophenotypes. Females with ASD who carried a greater number of ASD-associated risk alleles in the OXTR gene showed greater functional connectivity between the nucleus accumbens (NAcc; hub of the reward network) and subcortical brain areas important for motor learning. Relative to males with ASD, females with ASD and higher OXTR risk-allele-dosage showed increased connectivity between the NAcc, subcortical regions, and prefrontal brain areas involved in mentalizing. This increased connectivity between NAcc and prefrontal cortex mirrored the relationship between genetic risk and brain connectivity observed in neurotypical males showing that, under increased OXTR genetic risk load, females with ASD and neurotypical males displayed increased connectivity between reward-related brain regions and prefrontal cortex. These results indicate that females with ASD differentially modulate the effects of increased genetic risk on brain connectivity relative to males with ASD, providing new insights into the neurobiological mechanisms through which the female protective effect may manifest.

Memorialisation during COVID-19: implications for the bereaved, service providers and policy makers.

BACKGROUND: The aim of this rapid perspective review is to capture key changes to memorialisation practices resulting from social distancing rules implemented due to the ongoing COVID-19 pandemic. METHOD: As published peer-reviewed research pertaining to memorialisation practices during the COVID-19 pandemic is lacking, this rapid review includes academic literature from the pre-COVID-19 period and international media reports during the pandemic. FINDINGS: Changes to memorialisation practices were under way before COVID-19, as consumer preferences shifted towards secularisation and personalisation of ritual and ceremony. However, several key changes to memorialisation practices connected with body preparation, funerals, cremation, burials and rituals have taken place as a consequence of the COVID-19 pandemic. DISCUSSION: Although boundaries between public and private memorialisation practices were already blurred, the COVID-19 pandemic has accelerated this process. Without access to public memorialisation, practices are increasingly private in nature. A number of implications are considered for the bereaved, service providers and policy makers. CONCLUSION: Forms of memorialisation and bereavement support emerging during the pandemic that blend the public and the private are likely to persist in a post-pandemic world.

A health care labyrinth: perspectives of caregivers on the journey to accessing timely cancer diagnosis and treatment for children in India.

BACKGROUND: Cure rates for children with cancer in India lag behind that of high-income countries. Various disease, treatment and socio-economic related factors contribute to this gap including barriers in timely access of diagnostic and therapeutic care. This study investigated barriers to accessing care from symptom onset to beginning of treatment, from perspectives of caregivers of children with cancer in India. METHODS: Semi-structured in-depth interviews were conducted with caregivers of children (< 18 years) diagnosed with cancer in seven tertiary care hospitals across New Delhi and Hyderabad. Purposive sampling to saturation was used to ensure adequate representation of the child's gender, age, cancer type, geographical location and socioeconomic status. Interviews were audio recorded after obtaining informed consent. Thematic content analysis was conducted and organised using NVivo 11. RESULTS: Thirty-nine caregivers were interviewed, where three key themes emerged from the narratives: time intervals to definitive diagnosis and treatment, the importance of social supportive care and the overall accumulative impacts of the journey. There were two phases encapsulating the experiences of the family: referral pathways taken to reach the hospital and after reaching the hospital. Most caregivers, especially those from distant geographical areas had variable and inconsistent referral pathways partly due to poor availability of specialist doctors and diagnostic facilities outside major cities, influence from family or friends, and long travel times. Upon reaching the hospital, families mostly from public hospitals faced challenges navigating the hospital facilities, finding accommodation, and comprehending the diagnosis and treatment pathway. Throughout both phases, financial constraint was a recurring issue amongst low-income families. The caregiver's knowledge and awareness of the disease and health system, religious and social factors were also common barriers. CONCLUSION: This qualitative study highlights and explores some of the barriers to childhood cancer care in India. Our findings show that referral pathways are intrinsically linked to the treatment experience and there should be better recognition of the financial and emotional challenges faced by the family that occur prior to definitive diagnosis and treatment. This information would help inform various stakeholders and contribute to improved interventions addressing these barriers.

Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.

A Single-Cell Transcriptomic Atlas of Human Neocortical Development during Mid-gestation.

We performed RNA sequencing on 40,000 cells to create a high-resolution single-cell gene expression atlas of developing human cortex, providing the first single-cell characterization of previously uncharacterized cell types, including human subplate neurons, comparisons with bulk tissue, and systematic analyses of technical factors. These data permit deconvolution of regulatory networks connecting regulatory elements and transcriptional drivers to single-cell gene expression programs, significantly extending our understanding of human neurogenesis, cortical evolution, and the cellular basis of neuropsychiatric disease. We tie cell-cycle progression with early cell fate decisions during neurogenesis, demonstrating that differentiation occurs on a transcriptomic continuum; rather than only expressing a few transcription factors that drive cell fates, differentiating cells express broad, mixed cell-type transcriptomes before telophase. By mapping neuropsychiatric disease genes to cell types, we implicate dysregulation of specific cell types in ASD, ID, and epilepsy. We developed CoDEx, an online portal to facilitate data access and browsing.