Citations

AbstractThe COVID‐19 pandemic has caused significant shifts in patient care including a steep decline in ambulatory visits and a marked increase in the use of telemedicine. Infantile hemangiomas (IH) can require urgent evaluation and risk stratification to determine which infants need treatment and which can be managed with continued observation. For those requiring treatment, prompt initiation decreases morbidity and improves long‐term outcomes. The Hemangioma Investigator Group has created consensus recommendations for management of IH via telemedicine. FDA/EMA‐approved monitoring guidelines, clinical practice guidelines, and relevant, up‐to‐date publications regarding initiation and monitoring of beta‐blocker therapy were used to inform the recommendations. Clinical decision‐making guidelines about when telehealth is an appropriate alternative to in‐office visits, including medication initiation, dosage changes, and ongoing evaluation, are included. The importance of communication with caregivers in the context of telemedicine is discussed, and online resources for both hemangioma education and propranolol therapy are provided.

AbstractDeficient intake of micronutrients involved in one‐carbon metabolism (eg, choline, methionine, vitamin B12 and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under‐investigated in humans. We investigated the association between one‐carbon metabolism‐related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow‐up in the NIH‐AARP study. Dietary intakes and supplement use were ascertained at baseline using a food‐frequency questionnaire. Total intake (diet plus supplements) of the following one‐carbon metabolism‐related micronutrients were calculated: folate, methionine and vitamins B2 (riboflavin), B3 (niacin), B6 and B12. These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16‐year follow‐up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B3 intake was associated with a lower HCC risk (HRQ5 vs Q1 = 0.60; 95% CI = 0.42‐0.85; Ptrend = .008), and the association remained significant when all six micronutrients were examined simultaneously (HRQ5 vs Q1 = 0.32; 95% CI = 0.18‐0.55; Ptrend < .0001). Among participants with >3 years of follow‐up, higher total vitamin B3 intake was again associated with lower risk (HRQ5 vs Q1 = 0.37; 95% CI = 0.20‐0.68; Ptrend = .001), whereas higher total vitamin B6 intake was associated with higher risk (HRQ5 vs Q1 = 2.04; 95% CI = 1.02‐4.07; Ptrend = .04). Restricted cubic spline analyses showed a dose‐response inverse association between total vitamin B3 intake and HCC risk, and dose‐response positive association between total vitamin B6 intake and HCC risk. The study suggests that higher vitamin B3 intake is associated with lower HCC risk, whereas higher vitamin B6 intake is associated with increased risk.

We report a technique to simultaneously measure fractional synthesis rates (FSR) of several muscle proteins that facilitate further understanding of translational regulation, a key step involved in gene expression in a tissue. Skeletal muscle samples were collected from five rats following bolus injection of [ring 13 C 6 ] phenylalanine. Muscle proteins were fractionated by differential centrifugation followed by separation of individual proteins by high resolution two‐dimensional gel electrophoresis. We identified 60 mitochondrial and 30 non‐mitochondrial proteins by liquid chromatography tandem mass spectrometry. Isotope enrichment of these 90 proteins was measured by gas chromatography tandem mass spectrometry, and FSR was calculated using the muscle tissue fluid isotopic enrichment as the precursor. Approximately 25 fold differences in the FSR of muscle proteins were observed, (e.g. FSR of structural protein such as myosin heavy chain‐1 = 0.19 %/h ± 0.03 and tropomysin‐4 = 0.16 ± 03 and that of mitochondrial proteins such as cytochrome c oxidase Va = 0.64 ± 0.07 and dihydrolipoamide dehydrogenase = 4.3 %/h ± 0.53). The current approach, based on in‐vivo metabolic labeling, to simultaneously measure FSR of multiple muscle proteins offers tremendous opportunity to study the regulation of skeletal muscle mitochondrial and non‐mitochondrial protein synthesis in various physiologic and pathologic states. Funding: NIH RO1 DK41973

The worldwide prevalence of type 2 diabetes (T2D) is increasing. Despite normal to higher bone density, patients with T2D paradoxically have elevated fracture risk resulting, in part, from poor bone quality. Advanced glycation endproducts (AGEs) and inflammation as a consequence of enhanced receptor for AGE (RAGE) signaling are hypothesized culprits, although the exact mechanisms underlying skeletal dysfunction in T2D are unclear. Lack of inducible models that permit environmental (in obesity) and temporal (after skeletal maturity) control of T2D onset has hampered progress. Here, we show in C57BL/6 mice that a onetime pharmacological intervention (streptozotocin, STZ) initiated in adulthood combined with high-fat diet–induced (HFD-induced) obesity caused hallmark features of human adult-onset T2D, including prolonged hyperglycemia, insulin resistance, and pancreatic β cell dysfunction, but not complete destruction. In addition, HFD/STZ (i.e., T2D) resulted in several changes in bone quality that closely mirror those observed in humans, including compromised bone microarchitecture, reduced biomechanical strength, impaired bone material properties, altered bone turnover, and elevated levels of the AGE CML in bone and blood. Furthermore, T2D led to the premature accumulation of senescent osteocytes with a unique proinflammatory signature. These findings highlight the RAGE pathway and senescent cells as potential targets to treat diabetic skeletal fragility.

Abstract Background Intrathecal opioids are routinely administered during spinal anesthesia for postcesarean analgesia. The effectiveness of intrathecal morphine for postcesarean analgesia is well established, and the use of intrathecal hydromorphone is growing. No prospective studies have compared the effectiveness of equipotent doses of intrathecal morphine versus intrathecal hydromorphone as part of a multimodal analgesic regimen for postcesarean analgesia. The authors hypothesized that intrathecal morphine would result in superior analgesia compared with intrathecal hydromorphone 24 h after delivery. Methods In this single-center, double-blinded, randomized trial, 138 parturients undergoing scheduled cesarean delivery were randomized to receive 150 µg of intrathecal morphine or 75 µg of intrathecal hydromorphone as part of a primary spinal anesthetic and multimodal analgesic regimen; 134 parturients were included in the analysis. The primary outcome was the numerical rating scale score for pain with movement 24 h after delivery. Static and dynamic pain scores, nausea, pruritus, degree of sedation, and patient satisfaction were assessed every 6 h for 36 h postpartum. Total opioid consumption was recorded. Results There was no significant difference in pain scores with movement at 24 h (intrathecal hydromorphone median [25th, 75th] 4 [3, 5] and intrathecal morphine 3 [2, 4.5]) or at any time point (estimated difference, 0.5; 95% CI, 0 to 1; P = 0.139). Opioid received in the first 24 h did not differ between groups (median [25th, 75th] oral morphine milligram equivalents for intrathecal hydromorphone 30 [7.5, 45.06] vs. intrathecal morphine 22.5 [14.0, 37.5], P = 0.769). From Kaplan–Meier analysis, the median time to first opioid request was 5.4 h for hydromorphone and 12.1 h for morphine (log-rank test P = 0.200). Conclusions Although the hypothesis was that intrathecal morphine would provide superior analgesia to intrathecal hydromorphone, the results did not confirm this. At the doses studied, both intrathecal morphine and intrathecal hydromorphone provide effective postcesarean analgesia when combined with a multimodal analgesia regimen. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Abstract Background Close associations between insomnia with other clinical factors have been identified in migraine, but there have been few studies investigating associations between insomnia and clinical factors in patients with persistent post-traumatic headache (PPTH). The study objective was to contrast the severity of insomnia symptoms in PPTH, migraine, and healthy controls, and to identify factors associated with insomnia in patients with PPTH vs. migraine. Methods In this cross-sectional cohort study, 57 individuals with PPTH attributed to mild traumatic brain injury, 39 with migraine, and 39 healthy controls were included. Participants completed a detailed headache characteristics questionnaire, the Migraine Disability Assessment Scale (MIDAS), Insomnia Severity Index (ISI), Hyperacusis Questionnaire (HQ), Allodynia Symptom Checklist, Photosensitivity Assessment Questionnaire, Beck Depression Inventory (BDI), State-Trait Anxiety Inventory, Post-Traumatic Stress Disorder (PTSD) checklist, Ray Auditory Verbal Learning Test, and the Trail Making Test A and B to assess headache characteristics, disability, insomnia symptoms, sensory hypersensitivities, and neuropsychological factors. Fisher’s test and one-way ANOVA or Tukey’s Honest Significant Difference were used to assess group differences of categorical and continuous data. Stepwise linear regression analyses were conducted to identify clinical variables associated with insomnia symptoms. Results Those with PPTH had significantly higher ISI scores (16.7 ± 6.6) compared to migraine patients (11.3 ± 6.4) and healthy controls (4.1 ± 4.8) ( p < 0.001). For those with PPTH, insomnia severity was most strongly correlated with the BDI (Spearman's rho ( Common.EditSubmissionSteps.Transform.EquationText ) = 0.634, p < 0.01), followed by Trait Anxiety ( Common.EditSubmissionSteps.Transform.EquationText = 0.522, p < 0.01), PTSD ( Common.EditSubmissionSteps.Transform.EquationText = 0.505, p < 0.01), HQ ( Common.EditSubmissionSteps.Transform.EquationText = 0.469, p < 0.01), State Anxiety ( Common.EditSubmissionSteps.Transform.EquationText = 0.437, p < 0.01), and MIDAS scores ( Common.EditSubmissionSteps.Transform.EquationText = 0.364, p < 0.01). According to linear regression models, BDI, headache intensity, and hyperacusis scores were significantly positively associated with insomnia severity in those with PPTH, while only delayed memory recall was negatively associated with insomnia severity in those with migraine. Conclusions Insomnia symptoms were more severe in those with PPTH compared to migraine and healthy control cohorts. Depression, headache intensity, and hyperacusis were associated with insomnia in individuals with PPTH. Future studies should determine the bidirectional impact of treating insomnia and its associated symptoms.

Abstract Background: Pathogenic variants detected in multi-gene cancer predisposition panels are increasingly used to counsel women regarding their risk for breast cancer. However, the clinical implications of moderate penetrance genes (e.g. CHEK2, ATM) remain unclear. Breast MRI is indicated for women with a lifetime risk of breast cancer of &gt;20%, and polygenic risk scores (PRS) based on common variants discovered in recent genome-wide association studies (GWAS) may identify women with pathogenic variants in CHEK2 and ATM who are above or below this level of risk. PRS may also stratify carriers with substantially elevated lifetime risks of breast cancer. Previous work found that PRS modified breast cancer risk in carriers of pathogenic variant in BRCA1 or BRCA2, but the joint effects of pathogenic variants and PRS have not been studied in samples drawn from the general population. There is also no published study evaluating the effect of PRS among women with pathogenic variants in genes other than BRCA1/2 and CHEK2. Here, we evaluated the joint effects of PRS and pathogenic variants in ten established breast cancer predisposition genes in a population-based case-control sample. Method: We analyzed 43,144 non-Hispanic European-ancestry individuals (20,988 controls and 22,120 cases) drawn from 7 cohorts and 2 population-based case-control studies in the CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium. Targeted sequencing was performed using a dual bar-coded QIAseq panel of breast cancer predisposition genes. Variant calling was conducted with Haplotype Caller and Vardict. The PRS was calculated based on 106 common variants using effect estimates from the largest published breast cancer GWAS. Genetic status was evaluated for 10 breast cancer predisposition genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NF1, PALB2 and TP53. Lasso Penalized regression was performed to assess the combined effect on overall breast cancer of pathogenic variants and common variants (including main and interaction effects between age, family history, carrier status and PRS). The fraction of women at &gt;2-fold increased risk (which is associated with approximately 20% lifetime risk of breast cancer) was calculated for pathogenic variant carriers and non-carriers of different family history and age groups (&lt;40, 40-50, 50-60, 60-70, &gt;70yrs old). Results: Among non-carriers, one standard deviation change in the PRS was associated with a 1.63x change in odds of breast cancer. The best-fitting risk model did not include any PRS-by-carrier interaction terms, implying the relative risk gradient associated with PRS among women with pathogenic variants is similar to that among non-carriers. For carriers of pathogenic variants in moderate penetrance genes with no family history of breast cancer, the PRS can identify 60.6% of ATM pathogenic variant carriers and 30% of CHEK2 pathogenic variant carriers that have less than 2-fold risk of breast cancer; when carriers have a family history of breast cancer, the PRS can identify 30% of ATM pathogenic variant carriers and 11.8% of CHEK2 pathogenic variant carriers with less than 2-fold risk of breast cancer. Conclusion: In our large, population-based case-control study, the effect of the PRS among pathogenic variant carriers was not significantly different than among non-carriers. However, the PRS may be particularly important for estimating breast cancer risk among carriers of pathogenic variants in moderate penetrance genes such as CHEK2 and ATM, enabling a more precise approach for MRI screening strategy and breast cancer risk management. Citation Format: Chi Gao, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Kun Y. Lee, Jie Na, Nicholas J. Boddicker, Raed Samara, Paul Auer, Leslie Bernstein, Mia Gaudet, Amy Trentham-Dietz, Song Yao, Christopher Haiman, Janet E. Olson, Susan Neuhausen, Jeffrey N. Weitzel, David E. Goldgar, Susan Domchek, Katherine L. Nathanson, Fergus J. Couch, Peter Kraft, on behalf of the CARRIERS consortium. Polygenic risk scores provide clinically meaningful risk stratification among women carrying moderate penetrance pathogenic variants in breast cancer predisposition genes: Results from the CARRIERS study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-02.

Abstract Germline mutations in several cancer predisposition genes included in hereditary multigene testing panels have been associated with increased breast cancer risk. However, estimates of breast cancer risks for each gene have in large part been derived from studies of high-risk populations enriched for family history of breast and ovarian cancer, young age of breast cancer diagnosis, or founder mutations. The breast cancer risks associated with mutations in many of these genes in the general population remain to be clearly defined. As clinical hereditary cancer genetic testing is already provided to many women at increased risk and may soon be offered to all breast cancer patients, population-based risk estimates associated with predisposition gene mutations will be needed for appropriate clinical management of mutation carriers. The “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium of 17 cohort-based case-control, population-based case-control, and family studies focused on estimation of population-based breast cancer risks and penetrance analysis for mutations in known and candidate breast cancer predisposition genes. Germline DNA from 39486 breast cancer cases and 35868 matched controls was subjected to dual bar-coded QIAseq multiplex amplification of 1733 target regions in 37 predisposition genes. Products from sets of 768 samples were pooled and sequenced in each lane of a HiSeq 4000 system. Mutations were called by GATK Haplotype Caller and Verdict. High quality sequence data was obtained for 99.3% of target regions. Here we report on results from 34741 population-based breast cancer cases and 32728 matched unaffected controls. The mean age of breast cancer diagnosis for cases was 61.2 years and mean age for controls was 61.1 years. Overall, 20.9% of cases and 14.3% of controls had a family history of breast cancer. Furthermore, 74.3% of cases and 75.8% of controls were non-Hispanic white, whereas 13.3% of cases and 15.3% of controls were African American. Among cases with tumor information available, 81.7% were ER-positive and 7.7% were triple negative breast cancers (TNBC). We assessed mutation frequencies in 24 genes including 12 established breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, andTP53). The overall mutation frequency was 6.2% in cases and 2.7% in controls. Case-control association analysis after adjusting for study, age, family history of breast cancer, and race/ethnicity showed that BRCA1(OR=7.45; 95%CI:5.24-10.95) and BRCA2(OR=5.31; 95%CI:4.15-6.88) were associated with high risks of breast cancer in the general population. However, PALB2mutations were only associated with moderate risks (OR=3.63; 95%CI:2.57-5.26). ATMmutations conferred attenuated risks (OR=1.83; 95%CI:1.47-2.28) relative to studies of high-risk families or young onset breast cancers. NBNmutations were not associated with increased breast cancer risk. Mutations in BARD1, RAD51C, RAD51Dand XRCC2were specifically significantly associated with moderate risks of ER-negative breast cancer and TNBC, whereas mutations in ATM, CDH1and CHEK2were specifically significantly associated with ER-positive disease. On the basis of these findings age-related absolute breast cancer risks for commonly mutated genes were estimated. Overall, results from the CARRIERS study establish that mutations in predisposition genes are associated with lower risks of breast cancer in the general population than in enriched populations including high-risk families and young onset, bilateral, or multiple primary cases. We anticipate that the results from this study will inform cancer screening and other risk management strategies for women in the general population with mutations in predisposition genes. Citation Format: Fergus J Couch, Chunling Hu, Steven N Hart, Rohan Gnanaolivu, Kun Y Lee, Jie Na, Chi Gao, Nicholas J Boddicker, Bruce Eckloff, Raed Samara, Josh Klebba, Christine B Ambrosone, Hoda Anton-Culver, Paul Auer, Leslie Bernstein, Mia M Gaudet, Christopher Haiman, Esther M John, Susan Neuhausen, Janet E Olson, Tuya Pal, Julie R Palmer, Dale P Sandler, Jack A Taylor, Amy Trentham-Dietz, Celine M Vachon, Clarice Weinberg, Song Yao, Jeffrey N Weitzel, David E Goldgar, Susan M Domchek, Katherine L Nathanson, Peter Kraft, Eric C Polley. Population-based breast cancer risk estimates for predisposition gene mutations: Results from the CARRIERS study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-01.