Investing in Leadership Development: A Tool for Systems Change in the Community Health Center Field

Over the course of 12 years, the Blue Shield of California Foundation committed nearly $20 million to growing a pool of community health center leaders who were prepared to be effective agents of change in their organizations and in the safety net field. This signature investment, the Clinic Leadership Institute, was implemented in partnership with the Healthforce Center at University of California, San Francisco, in anticipation of a generation of California health center leaders beginning to transition into retirement. During the institute\u27s 10 cohorts, access to community health centers dramatically increased with the Affordable Care Act, and this — coupled with rising costs of health care — continued to underscore how crucial community health centers were to accessible and quality care for poor and underserved populations. A study spanning 10 cohorts of alumni found that the institute served a critical role in supporting community health center leaders and their organizations in navigating these changes, while also building alumni networks advocating for community health centers in county- and state-level policy. The program equipped 258 individuals to lead and deliver care in a field marked by continuous change, complexity, and mounting demand. Drawing on these findings, we make the case that investment in leadership development is a critical philanthropic tool for field building and, ultimately, systems change. We explore how the foundation made the most of this investment through intentional funding, design, and strategic considerations

Oral vitamin D supplementation induces transcriptomic changes in rectal mucosa that are linked to anti-tumour effects

Abstract Background The risk for several common cancers is influenced by the transcriptomic landscape of the respective tissue-of-origin. Vitamin D influences in vitro gene expression and cancer cell growth. We sought to determine whether oral vitamin D induces beneficial gene expression effects in human rectal epithelium and identify biomarkers of response. Methods Blood and rectal mucosa was sampled from 191 human subjects and mucosa gene expression (HT12) correlated with plasma vitamin D (25-OHD) to identify differentially expressed genes. Fifty subjects were then administered 3200IU/day oral vitamin D3 and matched blood/mucosa resampled after 12 weeks. Transcriptomic changes (HT12/RNAseq) after supplementation were tested against the prioritised genes for gene-set and GO-process enrichment. To identify blood biomarkers of mucosal response, we derived receiver-operator curves and C-statistic (AUC) and tested biomarker reproducibility in an independent Supplementation Trial (BEST-D). Results Six hundred twenty-nine genes were associated with 25-OHD level (P < 0.01), highlighting 453 GO-term processes (FDR<0.05). In the whole intervention cohort, vitamin D supplementation enriched the prioritised mucosal gene-set (upregulated gene-set P < 1.0E−07; downregulated gene-set P < 2.6E−05) and corresponding GO terms (P = 2.90E−02), highlighting gene expression patterns consistent with anti-tumour effects. However, only 9 individual participants (18%) showed a significant response (NM gene-set enrichment P < 0.001) to supplementation. Expression changes in HIPK2 and PPP1CC expression served as blood biomarkers of mucosal transcriptomic response (AUC=0.84 [95%CI 0.66–1.00]) and replicated in BEST-D trial subjects (HIPK2 AUC=0.83 [95%CI 0.77–0.89]; PPP1CC AUC=0.91 [95%CI 0.86–0.95]). Conclusions Higher plasma 25-OHD correlates with rectal mucosa gene expression patterns consistent with anti-tumour effects, and this beneficial signature is induced by short-term vitamin D supplementation. Heterogenous gene expression responses to vitamin D may limit the ability of randomised trials to identify beneficial effects of supplementation on CRC risk. However, in the current study blood expression changes in HIPK2 and PPP1CC identify those participants with significant anti-tumour transcriptomic responses to supplementation in the rectum. These data provide compelling rationale for a trial of vitamin D and CRC prevention using easily assayed blood gene expression signatures as intermediate biomarkers of response

A feasibility study of perioperative vitamin D supplementation in patients undergoing colorectal cancer resection

BackgroundVitamin D supplementation improves colorectal cancer (CRC) survival outcomes in randomized trials. The aim of this study was to test the feasibility, safety and efficacy of vitamin D supplementation in the pre- and perioperative period in patients undergoing CRC surgery.MethodsPatients were given 3200IU oral cholecalciferol (D3) per day perioperatively. Serial serum 25-hydroxyvitamin (25OHD) was measured by liquid chromatography tandem mass spectrometry and compared to untreated CRC controls. 25OHD and C-reactive protein (CRP) levels were compared using adjusted generalized linear mixed-effects models.ResultsA total of 122 patients underwent serial perioperative sampling, including 41 patients given high-dose perioperative supplementation. Supplementation was well-tolerated with no adverse or serious adverse events related to supplementation reported. Pre-operative supplementation increased 25OHD levels on the day of surgery (103.9 vs. 42.5 nmol/l, P = 8.2E–12). Supplementation increased 25OHD levels at all post-operative timepoints (P &lt; 0.001) and attenuated the post-operative drop in 25OHD (46 vs. 24% drop, P = 3.0E–4). Rate of vitamin D peri-operative insufficiency was significantly less in those on supplementation (e.g., day 3–5, 14 vs. 84%, P = 1.41E–08), with multivariate modeling across all timepoints indicating a ∼59 nmol/l higher 25OHD compared to control patients (P = 3.7E–21). Post-operative CRP was lower in patients taking supplementation (e.g., day 3–5 timepoint; 129 vs. 81 mg/l, P = 0.04).ConclusionHigh dose pre-operative vitamin D supplementation is associated with higher perioperative 25OHD levels, lower rates of vitamin D insufficiency and reduced early post-operative CRP. Alongside published evidence for a beneficial effect of vitamin D on CRC survival outcomes, these novel findings provide strong rationale for early initiation of vitamin D supplementation after a diagnosis of CRC

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development

Baboon syndrome: an unusual complication arising from antibiotic treatment of tonsillitis and review of the literature

A 40-year-old man presented with sore throat and fevers associated with bilaterally enlarged and inflamed tonsils. A clinical diagnosis of tonsillitis was made and the patient received intravenous benzylpenicillin. Over subsequent days, the patient developed a macular rash over both groins, buttocks and axillae, with necrotic patches in the groins. An assumptive diagnosis of necrotising fasciitis was made. The patient underwent urgent groin biopsy and was started on broad spectrum antibiotics. No organisms were seen on Gram stain. Following a multidisciplinary discussion, the patient was diagnosed with baboon syndrome (symmetrical drug-related intertriginous and flexural exanthema). He was treated with oral steroid along with topical agents. Baboon syndrome can develop following penicillin administration. Given the widespread use of penicillin antibiotics to treat tonsillitis and many other conditions, it is important that medical staff recognise the side effects of these medications

Research data supporting "Synchrotron analysis of toughness anomalies in nanostructured bainite"

A .eps file of the micrograph presented in Figure 2. Igor Pro .pxp files containing all of the experimental data used to create the graphs presented in Figures 3-9. Note: Igor Pro is a commercially available software package - available at https://www.wavemetrics.com/products/igorpro/igorpro.htmThis work was supported by the EPSRC [grant numbers EP/H500375/1 and EP/I02249X/1]