Health, education, and social care provision after diagnosis of childhood visual disability

Aim: To investigate the health, education, and social care provision for children newly diagnosed with visual disability.Method: This was a national prospective study, the British Childhood Visual Impairment and Blindness Study 2 (BCVIS2), ascertaining new diagnoses of visual impairment or severe visual impairment and blindness (SVIBL), or equivalent vi-sion. Data collection was performed by managing clinicians up to 1-year follow-up, and included health and developmental needs, and health, education, and social care provision.Results: BCVIS2 identified 784 children newly diagnosed with visual impairment/SVIBL (313 with visual impairment, 471 with SVIBL). Most children had associated systemic disorders (559 [71%], 167 [54%] with visual impairment, and 392 [84%] with SVIBL). Care from multidisciplinary teams was provided for 549 children (70%). Two-thirds (515) had not received an Education, Health, and Care Plan (EHCP). Fewer children with visual impairment had seen a specialist teacher (SVIBL 35%, visual impairment 28%, χ2p < 0.001), or had an EHCP (11% vs 7%, χ2p < 0 . 01).Interpretation: Families need additional support from managing clinicians to access recommended complex interventions such as the use of multidisciplinary teams and educational support. This need is pressing, as the population of children with visual impairment/SVIBL is expected to grow in size and complexity.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Lung Basal Stem Cells Rapidly Repair DNA Damage Using the Error-Prone Nonhomologous End-Joining Pathway

Lung squamous cell carcinoma (SqCC), the second most common subtype of lung cancer, is strongly associated with tobacco smoking and exhibits genomic instability. The cellular origins and molecular processes that contribute to SqCC formation are largely unexplored. Here we show that human basal stem cells (BSCs) isolated from heavy smokers proliferate extensively, whereas their alveolar progenitor cell counterparts have limited colony-forming capacity. We demonstrate that this difference arises in part because of the ability of BSCs to repair their DNA more efficiently than alveolar cells following ionizing radiation or chemical-induced DNA damage. Analysis of mice harbouring a mutation in the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key enzyme in DNA damage repair by nonhomologous end joining (NHEJ), indicated that BSCs preferentially repair their DNA by this error-prone process. Interestingly, polyploidy, a phenomenon associated with genetically unstable cells, was only observed in the human BSC subset. Expression signature analysis indicated that BSCs are the likely cells of origin of human SqCC and that high levels of NHEJ genes in SqCC are correlated with increasing genomic instability. Hence, our results favour a model in which heavy smoking promotes proliferation of BSCs, and their predilection for error-prone NHEJ could lead to the high mutagenic burden that culminates in SqCC. Targeting DNA repair processes may therefore have a role in the prevention and therapy of SqCC

Multilevel perceptions of the virtual delivery of the University of California Diabetes Prevention Program on RE-AIM domains due to COVID-19 mandates.

BACKGROUND: The University of Californias Diabetes Prevention Program (UC DPP) Initiative was implemented across all 10 UC campuses in 2018. The COVID-19 pandemic and accompanying mandates required swift changes to program delivery, including pivoting from in-person to virtual delivery (i.e., Zoom). Our goal was to assess multilevel constituent perceptions of the use of a virtual platform to deliver UC DPP due to COVID-19 mandates. METHODS: We conducted qualitative interviews with 68 UC DPP participants, coordinators, and leaders to examine the use of virtual platform delivery on the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) of UC DPP. Transcripts were analyzed using rapid qualitative analysis and emergent themes were categorized using domains corresponding to RE-AIM framework. RESULTS: Among UC DPP participants (n = 42), virtual delivery primarily impacted perceptions of UC DPP effectiveness and implementation. Some participants perceived program effectiveness to be negatively impacted, given their preference for in-person sessions, which they felt provided more engagement, peer support, and accountability. Implementation challenges included problems with virtual format (e.g., Zoom fatigue); however, several benefits were also noted (e.g., increased flexibility, maintenance of DPP connections during campus closures). UC DPP coordinators (n = 18) perceived virtual delivery as positively impacting UC DPP reach, since virtual platforms provided access for some who could not participate in-person, and negatively impacting effectiveness due to reduced engagement and lower peer support. UC leaders (n = 8) perceived that use of the virtual format had a positive impact on reach (e.g., increased availability, accessibility) and negatively impacted effectiveness (e.g., less intensive interactions on a virtual platform). Across constituent levels, the use of a virtual platform had little to no impact on perceptions of adoption and maintenance of UC DPP. CONCLUSION: Perceptions of the reach, effectiveness, and implementation of UC DPP using a virtual platform varied across constituents, although all groups noted a potential negative impact on overall program effectiveness. Unanticipated program adaptations, including virtual delivery, present potential benefits as well as perceived drawbacks, primarily across the effectiveness domain. Understanding differential constituent perceptions of the impact of virtual delivery can help maximize RE-AIM and inform future UC DPP delivery strategies

Twelve-Month Reach and Effectiveness of a University-Based Diabetes Prevention Initiative.

INTRODUCTION: The University of California (UC) implemented the Diabetes Prevention Program (DPP) to address diabetes and obesity risk. This project examined the reach and effectiveness of this university-based DPP delivery approach. METHODS: This project compared 12-month weight change among three groups of UC beneficiaries with overweight/obesity: (1) those who received invitation letters and enrolled in UC DPP, (2) those mailed invitation letters but did not enroll, and (3) those who were not mailed letters and did not enroll (controls). Using 2012-2022 EHR, administrative and DPP cohort data, an interrupted time series was conducted in 2022-2023 to compare group differences in rate of weight change. RESULTS: Among 6,231 beneficiaries (132 UC DPP aware enrollees, 1,750 DPP aware non-enrollees, 4,349 controls), UC DPP enrollees were older (mean age 49), mostly women (76%), and more diverse (33% Asian, 8% Black, 20% Hispanic, 4% Multi/Other). Over 12 months of follow-up, UC DPP enrollee postenrollment rate of weight loss was -0.68 lbs./month. UC DPP enrollees had significantly greater weight change from pre- to post-enrollment than DPP aware non-enrollees (adjusted Δ-1.02 vs. Δ-0.07 lbs./month, difference= -0.95, p&lt;0.001). Weight change among all participants who received letters with/without DPP enrollment was similar to controls. CONCLUSIONS: UC DPP reached a diverse group and was effective for weight loss at 12-month follow-up. However, UC DPP invitation letters to raise prediabetes and DPP awareness were not associated with significant weight change in the absence of DPP enrollment. University-based approaches to DPP delivery are effective and may enhance reach of DPP among at-risk adults

Multilevel perceptions of the virtual delivery of the University of California Diabetes Prevention Program on RE-AIM domains due to COVID-19 mandates

BackgroundThe University of California’s Diabetes Prevention Program (UC DPP) Initiative was implemented across all 10 UC campuses in 2018. The COVID-19 pandemic and accompanying mandates required swift changes to program delivery, including pivoting from in-person to virtual delivery (i.e., Zoom). Our goal was to assess multilevel constituent perceptions of the use of a virtual platform to deliver UC DPP due to COVID-19 mandates.MethodsWe conducted qualitative interviews with 68 UC DPP participants, coordinators, and leaders to examine the use of virtual platform delivery on the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) of UC DPP. Transcripts were analyzed using rapid qualitative analysis and emergent themes were categorized using domains corresponding to RE-AIM framework.ResultsAmong UC DPP participants (n = 42), virtual delivery primarily impacted perceptions of UC DPP effectiveness and implementation. Some participants perceived program effectiveness to be negatively impacted, given their preference for in-person sessions, which they felt provided more engagement, peer support, and accountability. Implementation challenges included problems with virtual format (e.g., “Zoom fatigue”); however, several benefits were also noted (e.g., increased flexibility, maintenance of DPP connections during campus closures). UC DPP coordinators (n = 18) perceived virtual delivery as positively impacting UC DPP reach, since virtual platforms provided access for some who could not participate in-person, and negatively impacting effectiveness due to reduced engagement and lower peer support. UC leaders (n = 8) perceived that use of the virtual format had a positive impact on reach (e.g., increased availability, accessibility) and negatively impacted effectiveness (e.g., less intensive interactions on a virtual platform). Across constituent levels, the use of a virtual platform had little to no impact on perceptions of adoption and maintenance of UC DPP.ConclusionPerceptions of the reach, effectiveness, and implementation of UC DPP using a virtual platform varied across constituents, although all groups noted a potential negative impact on overall program effectiveness. Unanticipated program adaptations, including virtual delivery, present potential benefits as well as perceived drawbacks, primarily across the effectiveness domain. Understanding differential constituent perceptions of the impact of virtual delivery can help maximize RE-AIM and inform future UC DPP delivery strategies

Human lung BSC and AT2 populations have progenitor activity.

<p>(A) Representative images of colonies grown from lung epithelial subsets in a 3-D in vitro assay; a 64-y-old male current smoker. Black scale bar = 500 μm; white scale bar = 100 μm. (B) Representative immunofluorescence staining of keratin 5 (KRT5) (a 57-y-old male exsmoker) and pro-surfactant protein C (proSFTPC) (a 54-y-old female exsmoker) in BSC and AT2 colonies. <i>n</i> = 13 patients; 39–78 y old; current, ex-, and never smokers. Scale bar = 100 μm. (C) Colony-forming capacity of sorted lung epithelial cells; <i>n</i> = 24 patients for proximal lung samples and <i>n</i> = 27 patients for distal lung samples; 21–85 y old; male and female; never, ex-, and current smokers. Student’s <i>t</i> test. (D) Representative images of human BSC and AT2 cell colonies from an exsmoker patient (a 57-y-old male) compared to a never-smoker patient (a 71-y-old female). Scale bar = 500 μm. (E) Linear regression analysis of the number of human BSCs (r² = 0.2) or AT2 colonies (r² = 0.3) versus number of years of patient tobacco smoking. <i>n</i> = 21 patients for basal colonies and <i>n</i> = 23 patients for AT2 colonies, 21–83 y old, male and female. The underlying data for panels C and E can be found in the <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2000731#pbio.2000731.s009" target="_blank">S1 Data</a> file.</p

Human lung BSCs are the putative cells of origin of lung squamous cell carcinoma.

<p>(A) Representative histogram of intracellular DAPI staining of BSCs and AT2 cells isolated from a 56-y-old male exsmoker patient. Gates indicate 2N, 4N, and polyploid cells. (B) Proportion of polyploidy cells in the BSC and AT2 subsets. <i>n</i> = 3 patients (a 69-y-old female exsmoker, a 56-y-old male exsmoker, and a 70-y-old female exsmoker). Paired <i>t</i> test. (C) Boxplots of human lung BSC expression scores by lung tumour subtypes (ADC, adenocarcinoma; SCLC, small cell lung cancer; SqCC, squamous cell carcinoma). The width of each box indicates the sample size. (D) Barcode plot showing strong correlation of the human lung BSC expression signature with that of SqCCs (ROAST <i>p</i> = 0.0001). Genes are sorted left to right from most up- to most down-regulated in SqCC relative to all other cancer subtypes. Positive BSC signature genes are marked with vertical red bars, and negative signatures genes are marked in blue. Variable-height bars show log-fold-change strength for each signature gene. (E) Fold changes in the expression of genes frequently altered in lung SqCC between human BSCs and other human lung epithelial cell types. <i>n</i> = 3 patients (a 64-y-old male exsmoker, an 83-y-old male exsmoker, and a 53-y-old male current smoker). (F) Violin plots showing expression levels of <i>PRKDC</i> and <i>XRCC6</i> in normal lung tissue (<i>n</i> = 54), lung ADCs (<i>n</i> = 125), and lung SqCCs (<i>n</i> = 224) from The Cancer Genome Atlas (TCGA). Violin bodies show log2 counts per million (log CPM) expression values as smoothed densities. All pairwise <i>p</i>-values are <10⁻⁶ by moderated <i>t</i> tests. (G) Proportion of genome altered versus <i>PRKDC</i> and <i>XRCC6</i> expression levels in TCGA lung SqCC data (<i>n</i> = 179). Expression levels are split into quartiles. Significance was determined by Student’s <i>t</i> tests. The underlying data for panels A, B, C, D, E, and G can be found in the <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2000731#pbio.2000731.s009" target="_blank">S1 Data</a> file.</p

Mouse tracheal BSCs are less sensitive than alveolar cells to DNA damage-induced cell death.

<p>(A) Barcode plots showing strong correlation of mouse and human expression signatures. The upper panel correlates the mouse tracheal BSC signature with that of human lung BSCs; the lower panel correlates the mouse alveolar cell signature with that of human AT2 cells. For each plot, genes are ordered left to right from most up-regulated to most down-regulated in human BSCs or AT2 cells, relative to all other cell populations. Positive mouse signature genes are marked with red vertical bars, and negative mouse signature genes with blue. Variable-height vertical bars show log-fold changes for the mouse signature genes. Worms show relative enrichment of mouse genes in the human ranked list. Rotation gene set tests give <i>p</i> = 0.0001 for each plot. (B) Immunofluorescence staining of γH2AX and T1α in alveoli or trachea of wild-type (WT) mice that are either nonirradiated or 1, 4, 8, 24, or 96 h post irradiation (6 Gy, top panel) or saline injected or 1, 4, 8, 24 or 96 h post bleomycin injection (40 mg/kg intravenously, bottom panel). T1α marks alveolar type 1 cells in the lung and BSCs in the trachea. Representative images of <i>n</i> = 3 mice at each time point. Scale bar = 20 μm. (C) FACS detection of dead cells in lung alveolar (EpCAM⁺) or tracheal BSCs (T1α⁺) isolated from WT mice 24 h post irradiation (6 Gy). <i>n</i> = 4–6 mice per group. Student’s <i>t</i> test. (D) Immunohistochemistry staining of Ki67 in alveoli or trachea of WT mice control or 4 h, 8 h, or 24 h post irradiation (6 Gy). Representative images for one of <i>n</i> = 3 mice at each time point. Scale bar = 20 μm. The underlying data for panel C can be found in the <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2000731#pbio.2000731.s009" target="_blank">S1 Data</a> file.</p

Human and mouse BSCs express markers of nonhomologous end joining.

<p>(A) Immunohistochemistry for RAD51, an early marker of homologous recombination, on WT mouse trachea and lung 1 h post γ-irradiation (6 Gy). The insert is a positive control, a mammary tumour from a MMTV-cre;Brca1^fl/flp53^+/- mouse. Black arrows indicate RAD51-positive nuclei. Representative images from <i>n</i> = 3 mice at each time point. Scale bar = 100 μm. (B) Expression of key genes in the NHEJ repair pathway in human BSCs and AT2 cells. <i>n</i> = 3 patients (a 64-y-old male exsmoker, an 83-y-old male exsmoker, and a 53-y-old male current smoker). RPKM, reads per kilobase per million mapped reads. Paired <i>t</i> test. (C) Immunofluorescence staining of phospho-DNA-PKcs and T1α in human airways and alveoli of three patients. Patient 1, a 56-y-old male smoker; patient 2, a 69-y-old female exsmoker; patient 3, a 70-y-old male smoker. Inset, isotype control. Scale bar = 20 μm. (D) Immunofluorescence staining of phospho-DNA-PKcs and T1α in trachea and lung of WT mice following IR (6 Gy). Representative images of one of <i>n</i> = 3 mice at each time point. Inset, isotype control. Scale bar = 20 μm. The underlying data for panel B can be found in the <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2000731#pbio.2000731.s009" target="_blank">S1 Data</a> file.</p