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Hypoglycemia, defined as a blood glucose < 2.2 mmol/L, is associated with death in pediatric cerebral malaria (CM). The optimal duration of glucose monitoring in CM is unknown. We collected data from 1,674 hospitalized Malawian children with CM to evaluate the association between hypoglycemia and death or neurologic disability in survivors. We assessed the optimal duration of routine periodic measurements of blood glucose. Children with hypoglycemia at admission had a 2.87-fold higher odds (95% CI: 1.35–6.09) of death and, if they survived, a 3.21-fold greater odds (95% CI: 1.51–6.86) of sequelae at hospital discharge. If hypoglycemia was detected at 6 hours but not at admission, there was a 7.27-fold higher odds of death (95% CI: 1.85–8.56). The presence of newly developed hypoglycemia after admission was not independently associated with neurological sequelae in CM survivors. Among all new episodes of blood sugar below a treatment threshold of 3.0 mmol/L, 94.7% occurred within 24 hours of admission. In those with blood sugar below 3.0 mmol/L in the first 24 hours, low blood sugar persisted or recurred for up to 42 hours. Hypoglycemia at admission or 6 hours afterward is strongly associated with mortality in CM. Children with CM should have 24 hours of post-admission blood glucose measurements. If a blood glucose less than the treatment threshold of 3.0 mmol/L is not detected, routine assessments may cease. Children who have blood sugar values below the treatment threshold detected within the first 24 hours should continue to have periodic glucose measurements for 48 hours post-admission.

The association between hyperglycemia and prostate cancer risk is inconsistent, and its association with prostate cancer mortality is understudied. Thus, we investigated the association between hyperglycemia and prostate cancer risk and mortality using multiple biomarkers simultaneously to classify hyper- and normoglycemia. We conducted a prospective analysis of 5,162 cancer-free men attending visit 2 (1990–1992) of the Atherosclerosis Risk in Communities (ARIC) study followed for total (N = 671) and lethal (N = 69) prostate cancer incidence and prostate cancer mortality (N = 64) through 2012. Men without diagnosed diabetes were classified as normo- or hyperglycemic using joint categories of fasting glucose, glycated hemoglobin, and glycated albumin (or fructosamine) defined by clinical or research cutpoints. We evaluated the multivariable-adjusted association of hyperglycemia with prostate cancer incidence and mortality using Cox proportional hazards regression; men with diagnosed diabetes were included as a separate exposure category. Among 4,753 men without diagnosed diabetes, 61.5% were classified as having hyperglycemia (high on ≥1 biomarker). HbA1c and glycated albumin together classified 61.9% of 1,736 men with normal fasting glucose as normoglycemic. Compared with men who were normal on all three biomarkers, men who were high on ≥1 biomarker had an increased risk of lethal [HR, 2.50; 95% confidence interval (CI), 1.12–5.58] and fatal (HR, 3.20; 95% CI, 1.26–8.48) disease, but not total prostate cancer incidence (HR, 0.98; 95% CI, 0.81–1.20); associations were similar including fructosamine instead of glycated albumin. Our findings indicate hyperglycemia is associated with an increased risk of lethal and fatal prostate cancer, but not total prostate cancer incidence.

Odds ratios (OR) and 95% confidence intervals (CI) for the association between body mass index (BMI) category and telomere variability* in prostate cancer cells overall and stratified by prostate cancer aggressiveness at surgery among men surgically treated for prostate cancer at Johns Hopkins Hospital, 1992 to 2016.

Supplemental Table 1: Association between lipid-lowering medication use and incident prostate cancer by frequency of routine physical examinations, and among participants who had health insurance or had private health insurance and/or Medicare, men in ARIC (1990-2012). Supplemental Table 2: Association between lipid-lowering medication use and fatal prostate cancer stratified by routine physical examination, and among participants who had health insurance or had private health insurance and/or Medicare, men in ARIC (1990-2012)

Supplemental methods, results from sensitivity analyses, and restricted cubic splines.

In our prior studies, obesity was associated with shorter telomeres in prostate cancer-associated stromal (CAS) cells, and shorter CAS telomeres were associated with an increased risk of prostate cancer death. To determine whether the association between obesity and shorter CAS telomeres is replicable, we conducted a pooled analysis of 790 men who were surgically treated for prostate cancer, whose tissue samples were arrayed on five tissue microarray (TMA) sets. Telomere signal was measured using a quantitative telomere-specific FISH assay and normalized to 4′,6-diamidino-2-phenylindole for 351 CAS cells (mean) per man; men were assigned their median value. Weight and height at surgery, collected via questionnaire or medical record, were used to calculate body mass index (BMI; kg/m2) and categorize men as normal (T2), obese men had a 3-fold increased odds of short CAS telomeres (OR: 3.06; 95% confidence interval: 1.07–8.75; Ptrend = 0.045) when compared with normal weight men. Telomere shortening in prostate stromal cells may be one mechanism through which lifestyle influences lethal prostate carcinogenesis.Prevention Relevance:This study investigates a potential mechanism underlying the association between obesity and prostate cancer death. Among men with aggressive prostate cancer, obesity was associated with shorter telomeres prostate cancer associated stromal cells, and shorter CAS telomeres have been associated with an increased risk of prostate cancer death.

PurposeCurrent biomarkers are inadequate prognostic predictors in localized prostate cancer making treatment decision-making challenging. Previously, we observed that the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer-associated stromal cells – the telomere biomarker – is strongly associated with progression to metastasis and prostate cancer death after prostatectomy independent of currently used pathologic indicators.Experimental DesignWe optimized our method allowing for semi-automated telomere length determination in single cells in fixed tissue, and tested the telomere biomarker in tissue microarrays from five cohort studies of men surgically treated for clinically localized disease (N=2,255). We estimated the relative risk (RR) of progression to metastasis (N=311) and prostate cancer death (N=85) using models appropriate to each study’s design adjusting for age, prostatectomy stage, and tumor grade, which then we meta-analyzed using inverse variance weights.ResultsCompared with men who had less variable telomere length among prostate cancer cells and longer telomere length in prostate cancer-associated stromal cells, men with the combination of more variable and shorter telomere length, had 3.76-times the risk of prostate cancer death (95% CI 1.37-10.3; p=0.01) and had 2.23-times the risk of progression to metastasis (95% CI 0.99-5.02, P=0.05). The telomere biomarker was associated with prostate cancer death in men with intermediate risk disease (Grade Groups 2/3: RR=9.18, 95% CI 1.14- 74.0, p=0.037) and with PTEN intact tumors (RR=6.74, 95% CI 1.46-37.6, p=0.015).ConclusionsThe telomere biomarker is robust and associated with poor outcome independent of current pathologic indicators in surgically-treated men.Translational RelevanceCurrent prognostic biomarkers in localized prostate cancer are inadequate imperfect predictors; therefore, new biomarkers are needed to improve the prognostic classification and management of these patients. In a five-cohort study, we confirmed that the tissue-based telomere biomarker – the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer-associated stromal cells – was associated with progression to metastasis and prostate cancer death independent of currently used prognostic indicators after prostatectomy for clinically-localized disease. Importantly, the telomere biomarker was associated with poor outcome in men with intermediate risk disease, as well as in men with intact PTEN tumors. Thus, this tissue-based telomere biomarker has the translational potential to improve treatment and surveillance decision-making.

Telomeres, the repetitive DNA elements at chromosome ends, are pivotal for maintenance of genome integrity. Previous studies from our group and others have highlighted the translational potential of tissue-based telomere length measurements to address the clinical challenge of improving diagnosis, individualized risk stratification, and accurate prognostication of different diseases. Here, we describe a high-throughput method that quantitates cell type-specific telomere lengths at a single cell level in archival tissues from patient cohorts for research on prognosis. This approach is based on telomere-specific fluorescence in situ hybridization (FISH) combined with multiplex immunostaining for cell type-specific antibodies, followed by semi-automated slide scanning and multi-channel acquisition of fluorescent images using the TissueFAXS Plus microscopy workstation and TissueQuest software (TissueGnostics). Here, we demonstrate that this method is sufficiently robust and reproducible to detect biologically significant differences in telomere lengths in archived tissues either on whole slides or sampled across tissue microarrays, which is essential when assessing prognosis in large patient cohorts.

OBJECTIVE Despite the emotional challenges of parental adjustment to a child’s type 1 diabetes diagnosis and the unique complexities of early childhood, there are few programs designed to meet the needs of parents of young children at new onset. This study evaluated First STEPS (Study of Type 1 in Early childhood and Parenting Support), a stepped-care behavioral intervention designed to support parents’ psychosocial functioning and promote children’s glycemic outcomes. RESEARCH DESIGN AND METHODS Using a two-site randomized clinical trial design, parents (n = 157) of children aged 1–6 years completed baseline data within 2 months of diabetes diagnosis and were randomly assigned to intervention (n = 115) or usual care (n = 42) for 9 months. Intervention steps included: 1) peer parent coaching, with step-ups to 2) structured behavioral counseling and 3) professional consultations with a diabetes educator and psychologist, based on parent mood and child HbA1c. Participants completed follow-ups at 9 and 15 months postrandomization. Primary outcomes were parent depressive symptoms and child HbA1c. RESULTS Depressive symptoms improved in both groups, and intervention parents had significantly lower depressive symptoms at the 9- and 15-month follow-ups compared with usual care. HbA1c decreased in both groups, but there were no between-group differences at 9 or 15 months. CONCLUSIONS First STEPS improved parents’ mood following young children’s type 1 diabetes diagnosis. Results indicate likely benefits of parent coach support, supplemented by intervention intensifications, including behavioral intervention and diabetes education. This model has high potential for patient engagement. The absence of a medical intervention component may explain null findings for HbA1c; incorporating targeted behavioral support for intensive diabetes treatment may maximize intervention impact.