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Folic acid supplementation is recommended during pregnancy to support healthy fetal development; (6 S)-5-methyltetrahydrofolic acid ((6 S)-5-MTHF) is available in some commercial prenatal vitamins as an alternative to folic acid, but its effect on blood folate status during pregnancy is unknown. To address this, we randomised sixty pregnant individuals at 8–21 weeks' gestation to 0·6 mg/d folic acid or (6 S)-5-MTHF × 16 weeks. Fasting blood specimens were collected at baseline and after 16 weeks (endline). Erythrocyte and serum folate were quantified via microbiological assay (as globally recommended) and plasma unmetabolised folic acid (UMFA) via LC-MS/MS. Differences in biochemical folate markers between groups were explored using multivariable linear/quantile regression, adjusting for baseline concentrations, dietary folate intake and gestational weeks. At endline (n 54), the mean values and standard deviations (or median, inter-quartile range) of erythrocyte folate, serum folate and plasma UMFA (nmol/l) in those supplemented with (6 S)-5-MTHF v. folic acid, respectively, were 1826 (sd 471) and 1998 (sd 421); 70 (sd 13) and 78 (sd 17); 0·5 (0·4, 0·8) and 1·3 (0·9, 2·1). In regression analyses, erythrocyte and serum folate did not differ by treatment group; however, concentrations of plasma UMFA in pregnancy were 0·6 nmol/l higher (95 % CI 0·2, 1·1) in those supplementing with folic acid as compared with (6 S)-5-MTHF. In conclusion, supplementation with (6 S)-5-MTHF may reduce plasma UMFA by ∼50 % as compared with supplementation with folic acid, the biological relevance of which is unclear. As folate is currently available for purchase in both forms, the impact of circulating maternal UMFA on perinatal outcomes needs to be determined. [ABSTRACT FROM AUTHOR]

During the coronavirus disease 2019 (COVID-19) pandemic, providers and patients must engage in shared decision making regarding the pros and cons of early versus delayed interventions for localized skin cancer. Patients at highest risk of COVID-19 complications are older; are immunosuppressed; and have diabetes, cancer, or cardiopulmonary disease, with multiple comorbidities associated with worse outcomes. Physicians must weigh the patient's risk of COVID-19 complications in the event of exposure against the risk of worse oncologic outcomes from delaying cancer therapy. Herein, the authors have summarized current data regarding the risk of COVID-19 complications and mortality based on age and comorbidities and have reviewed the literature assessing how treatment delays affect oncologic outcomes. They also have provided multidisciplinary recommendations regarding the timing of local therapy for early-stage skin cancers during this pandemic with input from experts at 11 different institutions. For patients with Merkel cell carcinoma, the authors recommend prioritizing treatment, but a short delay can be considered for patients with favorable T1 disease who are at higher risk of COVID-19 complications. For patients with melanoma, the authors recommend delaying the treatment of patients with T0 to T1 disease for 3 months if there is no macroscopic residual disease at the time of biopsy. Treatment of tumors ≥T2 can be delayed for 3 months if the biopsy margins are negative. For patients with cutaneous squamous cell carcinoma, those with Brigham and Women's Hospital T1 to T2a disease can have their treatment delayed for 2 to 3 months unless there is rapid growth, symptomatic lesions, or the patient is immunocompromised. The treatment of tumors ≥T2b should be prioritized, but a 1-month to 2-month delay is unlikely to worsen disease-specific mortality. For patients with squamous cell carcinoma in situ and basal cell carcinoma, treatment can be deferred for 3 months unless the individual is highly symptomatic. [ABSTRACT FROM AUTHOR]

Background: Long-chain n-6 and n-3 PUFAs are important for growth and development. However, little is known about requirements and current dietary intakes of these fatty acids in toddlers.Objectives: This study assessed dietary intakes of n-6 and n-3 PUFAs and determined the relation to circulating PUFAs in toddlers at ages 1 and 2 y.Methods: This is a secondary analysis of data from toddlers enrolled in a double-blind randomized controlled trial of arachidonic acid (ARA) and DHA supplementation between ages 1 and 2 y. Dietary intakes of fatty acids were estimated by 3-d food records, and fatty acid composition in plasma total phospholipids, red blood cell phosphatidylethanolamine (PE), and phosphatidylcholine (PC) were assessed by GC at baseline in all subjects (n = 110; mean age 1.12 y; 64% male) and in the control subjects at 2 y (n = 43).Results: The dietary intakes of ARA, EPA, and DHA at age 1 y (baseline) were [mean (median)] 36.8 (30.0), 16.0 (0.00), and 31.1 (10.0) mg/d, respectively. Dietary intakes increased to 52.7 (45.0), 35.8 (0.00), and 64.8 (20.0) mg/d, respectively, at age 2 y (P < 0.05). The predominant dietary source of EPA and DHA was fish/seafood; eggs were an important source of ARA and DHA. Dietary DHA intakes were positively associated with plasma PE and PC DHA (P < 0.05). No relations between dietary ARA intakes and plasma PE and PC ARA (P > 0.05) were observed.Conclusions: These findings suggest that most toddlers are not meeting the recommendation for dietary PUFA intakes and that higher dietary DHA intakes are reflected in plasma PE and PC DHA composition. Further work is required to investigate a biomarker for dietary ARA intake. This trial is registered at clinicaltrials.gov as NCT01263912. [ABSTRACT FROM AUTHOR]

Objectives: As a follow-up to the CHIPS trial (Control of Hypertension In Pregnancy Study) of 'less tight' (versus 'tight') control of maternal blood pressure in pregnancy, CHIPS-Child investigated potential developmental programming of maternal blood pressure control in pregnancy, by examining measures of postnatal growth rate and hypothalamic-pituitary adrenal (HPA) axis activation.Methods: CHIPS follow-up was extended to 12 ± 2 months corrected post-gestational age for anthropometry (weight, length, head/waist circumference). For eligible children with consent for a study visit, we collected biological samples (hair/buccal samples) to evaluate HPA axis function (hair cortisol levels) and epigenetic change (DNA methylation analysis of buccal cells). The primary outcome was 'change in z-score for weight' between birth and 12 ± 2 mos. Secondary outcomes were hair cortisol and genome-wide DNA methylation status.Results: Of 683 eligible babies, 183 (26.8%) were lost to follow-up, 83 (12.2%) declined, 3 (0.4%) agreed only to ongoing contact, and 414 (60.6%) consented. 372/414 (89.9%) had weight measured at 12mos. In 'less tight' (vs. 'tight') control, the primary outcome was similar [-0.26 (-0.53, +0.01); p = 0.14, padjusted = 0.06]; median (95% confidence interval) hair cortisol (N = 35 samples) was lower [-496 (-892, -100) ng/g; p = 0.02], and buccal swab DNA methylation (N = 16 samples) was similar. No differences in growth rate could be demonstrated up to 5 years.Conclusions: Results demonstrate no compelling evidence for developmental programming of growth or the HPA axis. Clinicians should look to the clinical findings of CHIPS to guide practice. Researchers should seek to replicate these findings and extend outcomes to paediatric blood pressure and neurodevelopment. [ABSTRACT FROM AUTHOR]

Background: Choline is an important nutrient during development. However, there are limited data on dietary choline intake and status in toddlers and the relation to neurodevelopmental outcomes.Objective: This study assessed dietary choline intake and status in healthy toddlers at ages 1 and 2 y and determined the relation to neurodevelopmental outcomes.Methods: This is a secondary analysis of data from healthy toddlers enrolled in a double-blind, randomized controlled trial of long-chain polyunsaturated fatty acid supplementation between ages 1 and 2 y. Dietary intakes of betaine and choline were estimated by 3-d food records; plasma free choline, betaine, and dimethylglycine were quantified by liquid chromatography-tandem mass spectrometry. Developmental outcomes were assessed at age 2 y with the use of the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), Cognitive and Language composites, and the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery-VMI).Results: The mean ± SD daily intake for total choline at age 1 y was 174 ± 56.2 mg/d and increased (P < 0.001) to 205 ± 67.5 mg/d at age 2 y. At ages 1 and 2 y, 71.8% and 55.8%, respectively, of toddlers did not meet the recommended 200-mg/d Adequate Intake (AI) for dietary choline. At age 1 y, mean ± SD plasma free choline, betaine, and dimethylglycine concentrations were 10.4 ± 3.3, 41.1 ± 15.4, and 4.1 ± 1.9 µmol/L, respectively. Plasma free choline (8.5 ± 2.3 µmol/L) and dimethylglycine (3.2 ± 1.3 µmol/L) concentrations were lower (P < 0.001) at age 2 y. Plasma betaine concentrations were positively associated with the Beery-VMI (β = 0.270; 95% CI: 0.026, 0.513; P = 0.03) at age 2 y.Conclusions: These findings suggest that most toddlers are not meeting the recommended AI for dietary choline and that higher plasma betaine concentrations are associated with better visual-motor development at age 2 y. Further work is required to investigate choline metabolism and its role in neurodevelopment in toddlers. The trial is registered at clinicaltrials.gov as NCT01263912. [ABSTRACT FROM AUTHOR]

Background: Folic acid fortification of grains is mandated in many countries to prevent neural tube defects. Concerns regarding excessive intakes of folic acid have been raised. A synthetic analog of the circulating form of folate, l-5-methyltetrahydrofolate (l-5-MTHF), may be a potential alternative.Objective: The objective of this study was to determine the effects of folic acid or l-5-MTHF supplementation on blood folate concentrations, methyl nutrient metabolites, and DNA methylation in women living in Malaysia, where there is no mandatory fortification policy.Methods: In a 12-wk, randomized, placebo-controlled intervention trial, healthy Malaysian women (n = 142, aged 20-45 y) were randomly assigned to receive 1 of the following supplements daily: 1 mg (2.27 μmol) folic acid, 1.13 mg (2.27 μmol) l-5-MTHF, or a placebo. The primary outcomes were plasma and RBC folate and vitamin B-12 concentrations. Secondary outcomes included plasma total homocysteine, total cysteine, methionine, betaine, and choline concentrations and monocyte long interspersed nuclear element-1 (LINE-1) methylation.Results: The folic acid and l-5-MTHF groups had higher (P < 0.001) RBC folate (mean ± SD: 1498 ± 580 and 1951 ± 496 nmol/L, respectively) and plasma folate [median (25th, 75th percentiles): 40.1 nmol/L (24.9, 52.7 nmol/L) and 52.0 nmol/L (42.7, 73.1 nmol/L), respectively] concentrations compared with RBC folate (958 ± 345 nmol/L) and plasma folate [12.6 nmol/L (8.80, 17.0 nmol/L)] concentrations in the placebo group at 12 wk. The l-5-MTHF group had higher RBC folate (1951 ± 496 nmol/L; P = 0.003) and plasma folate [52.0 nmol/L (42.7, 73.1 nmol/L); P = 0.023] at 12 wk than did the folic acid group [RBC folate, 1498 ± 580 nmol/L; plasma folate, 40.1 nmol/L (24.9, 52.7 nmol/L)]. The folic acid and l-5-MTHF groups had 17% and 15%, respectively, lower (P < 0.001) plasma total homocysteine concentrations than did the placebo group at 12 wk; there were no differences between the folic acid and l-5-MTHF groups. No differences in plasma vitamin B-12, total cysteine, methionine, betaine, and choline and monocyte LINE-1 methylation were observed.Conclusion: These findings suggest differential effects of l-5-MTHF compared with folic acid supplementation on blood folate concentrations but no differences on plasma total homocysteine lowering in Malaysian women. This trial was registered at clinicaltrials.gov as NCT01584050. [ABSTRACT FROM AUTHOR]

Context: Research shows an increased symptom burden in young adult (YA) cancer patients compared with their older adult counterpart. Objectives: The purpose of this study was to identify differences in clinical characteristics and related outcomes between YA and older adult cancer patients admitted for cancer-related pain. Materials and Methods: We retrospectively identified 190 hospitalized patients in a single academic center with admissions for cancer-related pain. Patients were grouped into either "young adult" (18–39) or "older adult" (>40) cohorts. We compared differences in patient characteristics and pain regimens. Results: Median oral morphine equivalent per 24 hours was higher in the YA group (194 mg vs. 70 mg, p = 0.010). Younger patients received patient-controlled analgesia (PCA) more frequently (p = 0.023). The number of palliative care consults and adjuvants prescribed did not differ between groups (p > 0.05), although YAs more frequently had an inpatient pain anesthesia consult (p = 0.047). Conclusion: Findings show increased opioid requirements and PCA use in YAs being treated for malignancy compared with their older adult counterpart. [ABSTRACT FROM AUTHOR]

Background and purpose To compare the pre-treatment brachytherapy plan verification by a physicist assisted by custom plan verification software (SAV) with those performed manually (MV). Materials and methods All HDR brachytherapy plans used for treatment in 2013, verified using either SAV or MV, were retrospectively reviewed. Error rate (number of errors/number of plans) was measured and verification time calculated. All HDR brachytherapy safety events recorded between 2010 and 2013 were identified. The rate of patient-related safety events (number of events/number of fractions treated) and the impact of SAV on the underlying errors were assessed. Results Three/106 errors (2.8%) were found in the SAV group and 24/273 (8.8%) in the MV group ( p = 0.046). The mean ±1 standard deviation plan verification time was 8.4 ± 4.0 min for SAV and 11.6 ± 5.3 for MV ( p = 0.006). Seven safety events out of 4729 fractions delivered (0.15%) were identified. Four events (57%) were associated with plan verification and could have been detected by SAV. Conclusions We found a safety event rate in HDR brachytherapy of 0.15%. SAV significantly reduced the number of undetected errors in HDR treatment plans compared to MV, and reduced the time required for plan verification. [ABSTRACT FROM AUTHOR]

Abstract: Infectious laryngotracheitis virus (ILTV) is an alphaherpesvirus that causes acute respiratory disease in poultry. Live attenuated ILTV vaccines have been used extensively to help control outbreaks of disease. Two Australian-origin attenuated vaccine strains, SA2 and A20 ILTV, are commercially available and are in frequent use in Australia. Both these vaccines are of chicken embryo origin (CEO). The A20 ILTV strain was developed from the SA2 ILTV strain by sequential passage of SA2 ILTV in tissue culture in order to reduce its residual virulence. Previous studies in our laboratories have demonstrated the greater attenuation of A20 ILTV under controlled experimental conditions, but the genetic basis of the in vivo phenotypes of A20 and SA2 ILTV has not been elucidated. In this study, the genetic differences between A20 and SA2 ILTV were examined by performing complete genome sequencing and comparative analysis. The genome sequences were also compared to a reference sequence from another CEO ILTV vaccine (Serva ILTV: GenBank accession number HQ_630064) of European-origin. Additional in ovo studies to assess cell to cell spread were performed in order to allow further comparisons of the pathogenicity of SA2 and A20 ILTV. The sequencing results showed that the genome sizes of SA2 and A20 ILTV were 152,975 and 152,978bp, respectively, while Serva ILTV had a genome size of 152,630bp. The genomes of SA2 and A20 ILTV shared 99.9% nucleotide sequence identity with each other, but only 99.2% identity with Serva ILTV. In complete genome alignments between SA2 and A20 ILTV, a total of 24 single nucleotide polymorphisms (SNPs) were identified, but only two of these were non-synonymous. These were located in the ORF B and UL15 genes. Four indels were detected in non-coding regions. The findings from this study demonstrate the general genetic stability of ILTV, but also show that non-synonymous changes in the ORF B and UL15 genes have arisen following tissue culture passage of SA2 ILTV to produce the A20 vaccine. It is likely that these non-synonymous changes are related to the greater attenuation of A20 ILTV compared to SA2 ILTV, and to the reduced ability of A20 ILTV to spread from cell to cell, as observed in this study. The results from this study also demonstrate the divergence between the genomes of the Australian-origin ILTV vaccine strains and the Serva vaccine strain. [Copyright &y& Elsevier]

Double-unit cord blood (DCB) grafts are a rapidly available stem cell source for adults with high-risk leukemias. However, how disease-free survival (DFS) after DCB transplantation (DCBT) compares to that of unrelated donor transplantation (URDT) is not fully established. We analyzed 166 allograft recipients (66 8/8 HLA–matched URDT, 45 7/8 HLA–matched URDT, and 55 DCBT) ages 16 to 60 years with high-risk acute leukemia or chronic myelogenous leukemia (CML). URDT and DCBT recipients were similar except DCBT recipients were more likely to have lower weight and non-European ancestry and to receive intermediate-intensity conditioning. All URDT recipients received a CD34 + cell–selected (T cell–depleted) graft. Overall, differences between the 3-year transplantation-related mortality were not significant (8/8 URDT, 18%; 7/8 URDT, 39%; and DCBT, 24%; P = .108), whereas the 3-year relapse risk was decreased after DCBT (8/8 URDT, 23%; 7/8 URDT, 20%; and DCBT 9%, P = .037). Three-year DFS was 57% in 8/8 URDT, 41% in 7/8 URDT, and 68% in DCBT recipients ( P = .068), and the 3-year DFS in DCBT recipients was higher than that of 7/8 URDT recipients ( P = .021). In multivariate analysis in acute leukemia patients, factors adversely associated with DFS were female gender (hazard ratio [HR], 1.68; P = .031), diagnosis of acute lymphoblastic leukemia (HR, 2.09; P = .004), and 7/8 T cell–depleted URDT (HR, 1.91; P = .037). High DFS can be achieved in adults with acute leukemia and CML with low relapse rates after DCBT. Our findings support performing DCBT in adults in preference to HLA-mismatched T cell–depleted URDT and suggest DCBT is a readily available alternative to T cell–depleted 8/8 URDT, especially in patients requiring urgent transplantation. [ABSTRACT FROM AUTHOR]

Methionine metabolism is regulated by folate, and both folate deficiency and abnormal hepatic methionine metabolism are recognized features of alcoholic liver disease (ALD). Previously, histological features of ALD were induced in castrated male micropigs fed diets containing ethanol at 40% of kilocalories for 12 months, whereas in male micropigs fed the same diets for 12 months abnormal methionine metabolism and hepatocellular apoptosis developed. Folate deficiency may promote the development of ALD by accentuating abnormal methionine metabolism. Intact male micropigs received eucaloric diets that were folate sufficient, folate deficient, or each containing 40% of kilocalories as ethanol for 14 weeks. Folate deficiency alone reduced hepatic folates by one half, and ethanol feeding alone reduced methionine synthase, S-adenosylmethionine (SAM), and glutathione (GSH) levels and elevated plasma malondialdehyde (MDA) levels. The combined regimen elevated plasma homocysteine, hepatic S-adenosylhomocysteine (SAH), urinary 8-hydroxy-2-deoxyguanosine (oxy8dG), an index of DNA oxidation, and serum aspartate aminotransferase (AST) levels. Terminal hepatic histopathologic characteristics included typical features of steatonecrosis and focal inflammation in pigs fed the combined diet, with no changes in the other groups. Hepatic SAM levels correlated with those of GSH, whereas urinary oxy8dG and plasma MDA levels correlated with the SAM:SAH ratio and to hepatic GSH. The results demonstrate the linkage of abnormal methionine metabolism to products of DNA and lipid oxidation and to liver injury. The finding of steatonecrosis and focal inflammation only in the combined diet group supports the suggestion that folate deficiency promotes and folate sufficiency protects against the early onset of methionine cycle–mediated ALD. [Copyright &y& Elsevier]

Purpose: A recent randomized controlled trial demonstrated that the addition of external beam radiation therapy (EBRT) to brachytherapy did not improve progression-free survival in select patients with intermediate-risk prostate cancer. We evaluated whether the addition of EBRT to brachytherapy improves prostate cancer-specific mortality (PCSM) for intermediate- and high-risk disease using a large national database.Methods and Materials: We identified 5836 patients in the Surveillance, Epidemiology, and End Results-Medicare linked database with a diagnosis of National Comprehensive Cancer Network intermediate-risk (Gleason score 7, prostate-specific antigen 10-20 ng/mL, or stage cT2b-T2c) or high-risk (Gleason score 8-10 or prostate-specific antigen >20 ng/mL and stage ≤cT3a) prostate cancer who had undergone brachytherapy, with or without EBRT and androgen deprivation therapy (ADT). Patients were diagnosed from 2004 through 2009. Intermediate-risk patients with Gleason score ≤3+4 and 1 intermediate-risk factor were considered favorable and all others unfavorable. We used multivariable Fine-Gray competing risks regression to study PCSM while adjusting for sociodemographic and clinical factors and ADT use.Results: Overall, 50.3% of intermediate- and high-risk patients who received brachytherapy and EBRT did not have significantly improved PCSM compared with that of the patients who received brachytherapy alone (adjusted hazard ratio [AHR] 1.46, 95% confidence interval [CI] 0.69-3.11; P=.322; 5-year PCSM 2.4% vs 1.0%). This lack of benefit was seen among favorable intermediate-risk (AHR 2.66, 95% CI 0.93-7.62, P=.069; 5-year PCSM 1.3% vs 0.6%), unfavorable intermediate-risk (AHR 0.68, 95% CI 0.16-2.96, P=.612; 5-year PCSM 1.0% vs 1.2%), and high-risk (AHR 1.82, 95% CI 0.67-4.98, P=.242; 5-year PCSM 5.3% vs 2.1%) subgroups.Conclusions: These results suggest that certain patients with intermediate- or high-risk prostate cancer treated with brachytherapy might not benefit from the addition of EBRT. A randomized controlled trial of brachytherapy plus ADT with or without EBRT for unfavorable intermediate- and favorable high-risk organ-confined prostate cancer should be undertaken. [ABSTRACT FROM AUTHOR]

Purpose The relative use of brachytherapy (BT) for prostate cancer has declined in recent years. In this setting, we sought to determine whether the case mix of BT monotherapy–treated men has changed over time in terms of risk group composition. Methods and Materials The Surveillance, Epidemiology, and End Results database was used to identify 30,939 patients diagnosed with prostate adenocarcinoma between 2004 and 2011 who received BT monotherapy. The case mix of BT monotherapy patients was calculated by patient risk group and year of diagnosis. Results Between 2004 and 2011, the use of BT monotherapy declined overall. The relative percentage of men undergoing BT with low-risk disease declined by 4.5%, whereas the relative percentage of patients with intermediate-risk disease increased by 4.7%. Non-white patients and those from poorer counties did not show shifts in the risk group makeup of BT monotherapy patients, whereas white patients and those from wealthier counties did. Conclusions Although fewer patients with prostate cancer are undergoing BT monotherapy, men with intermediate-risk disease comprised a significantly larger portion of the BT case mix in 2011 compared with 2004. Future research efforts by brachytherapists should be directed toward improving BT technique, optimizing radiation doses, and obtaining long-term followup data for patients with intermediate-risk prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Brachytherapy (BT) monotherapy is a well-established treatment modality for favorable intermediate risk (FIR) prostate cancer. However, patients with unfavorable intermediate risk (UIR) disease are often recommended trimodality therapy involving BT, androgen deprivation therapy (ADT), and external beam radiation therapy (EBRT). We sought to investigate the relative benefit of supplemental therapies (ADT and/or EBRT) for FIR and UIR prostate cancer in a large dataset.Materials/methods: We identified 3,723 patients with intermediate risk prostate cancer treated with BT between 1997 and 2013, including 1,989 and 1,734 patients with FIR and UIR disease, respectively. For the FIR cohort, Fine and Gray's competing risks regression model was used to evaluate whether there was a difference in prostate cancer specific mortality (PCSM) between BT vs. BT + supplemental therapy (ADT, EBRT, or both). For the UIR cohort, this regression model was used to evaluate whether supplemental ADT, EBRT, or both decreased PCSM beyond BT alone. Both regression models were adjusted for clinical and treatment-related factors.Results: The median follow-up periods were 7.7 years (interquartile range: 5.4-10.5) for the FIR cohort and 7.8 years (interquartile range: 5.3-10.6) for the UIR cohort. For the FIR cohort, there was no difference in PCSM between BT monotherapy vs. BT + supplemental therapy (adjusted hazard ratio [AHR] = 1.70; 95% CI: 0.46-6.29; P = 0.43). For the UIR cohort, supplemental EBRT (AHR = 2.66; 95% CI: 1.12-6.34; P = 0.03), ADT (AHR = 0.96; 95% CI: 0.38-2.43; P = 0.93), or both (AHR = 1.46; 95% CI: 0.42-5.01; P = 0.55) were not associated with improved PCSM compared with BT alone.Conclusion: In our analysis, supplemental therapies did not offer an improvement in PCSM compared with BT alone for FIR or UIR prostate cancers. Further prospective clinical trials are required to determine whether BT monotherapy may be sufficient for a subset of patients with UIR disease. [ABSTRACT FROM AUTHOR]