Building trust and increasing inclusion in public health research: co-produced strategies for engaging UK ethnic minority communities in research.

Patient and public involvement and engagement (PPIE) is essential for improved research outcomes and reduced research waste. To be effective, PPIE should provide opportunities for diverse groups to contribute to all research stages. However, UK ethnic minority communities remain underrepresented in research. This article describes strategies adopted in a public health research project that were effective in building trust and increasing inclusion of ethnic minority communities. The study team of researchers and PPIE partners reflects lessons learnt during the project and describe six main strategies that built meaningful levels of trust and inclusion: 1) early start to recruitment of PPIE partners; 2) relationship-focused engagement; 3) co-production and consultation activities; 4) open communication and iterative feedback; 5) co-production of project closure activities, and; 6) diverse research team. Meaningful outcomes for the community included the involvement of people from ethnic minorities as research participants and PPIE partners, community wellbeing, co-production of public health recommendations co-presented at the UK Houses of Parliament, and consortium-wide impact evidenced by the enrolment of 51 active PPIE partners. PPIE partners reflect on their research involvement, offering advice to researchers and encouraging people from ethnic minority communities to take part in research. An important message from PPIE partners is that involvement should not be restricted to projects specific to ethnic minorities but become a routine part of general population research, recognising ethnic minorities as an integral part of UK society. In conclusion, this article demonstrates that with appropriate strategies, inclusion and diversity can be achieved in public health research. We recommend researchers, practitioners and policy makers adopt these strategies when planning their public health projects.

Inverse Association Between Gluteofemoral Obesity and Risk of Non-Cardia Gastric Intestinal Metaplasia.

BACKGROUND & AIMS: It is unclear whether obesity confers increased risk of non-cardia gastric adenocarcinoma and its precursor, gastric intestinal metaplasia. Here, we examined whether various dimensions of adiposity independently predispose to the development of non-cardia gastric intestinal metaplasia. METHODS: We compared data from 409 non-cardia gastric intestinal metaplasia cases and 1748 controls without any gastric intestinal metaplasia from a cross-sectional study at the VA Medical Center in Houston, Texas. Participants completed standardized questionnaires, underwent anthropometric measurements, and underwent a study endoscopy with gastric mapping biopsies. Non-cardia gastric intestinal metaplasia cases included participants with intestinal metaplasia on any non-cardia gastric biopsy. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) using logistic regression models. RESULTS: Increasing body mass index (BMI) was not associated with risk of non-cardia gastric intestinal metaplasia (per unit BMI adjusted OR, 0.98; 95% CI, 0.96-1.00). Similarly, we found no associations with increase in waist circumference (per 10-cm increase adjusted OR, 0.94; 95% CI, 0.87-1.03) and waist-to-hip ratio (WHR) (per unit WHR adjusted OR, 2.34; 95% CI, 0.37-14.7). However, there was a significant inverse association with gastric intestinal metaplasia and increasing hip circumference, reflecting gluteofemoral obesity (per 10-cm increase adjusted OR, 0.89; 95% CI, 0.80-0.98). The inverse association was observed for both extensive and focal gastric intestinal metaplasia. CONCLUSIONS: The independent dimensions of adiposity (BMI, waist circumference) are not associated with increased risk of non-cardia gastric intestinal metaplasia. The inverse association between gluteofemoral obesity and risk of gastric intestinal metaplasia warrants additional study.

Effects of heat stress on markers of skeletal muscle proteolysis in dairy cattle.

Heat stress (HS) markedly affects postabsorptive energetics and protein metabolism. Circulating urea nitrogen increases in multiple species during HS and it has been traditionally presumed to stem from increased skeletal muscle proteolysis; however, this has not been empirically established. We hypothesized HS would increase activation of the calpain and proteasome systems as well as increase degradation of autophagosomes in skeletal muscle. To test this hypothesis, lactating dairy cows (~139 d in milk; parity ~2.4) were exposed to thermal neutral (TN) or HS conditions for 7 d (8 cows/environment). To induce HS, cattle were fitted with electric blankets for the duration of the heating period and the semitendinosus was biopsied on d 7. Heat stress increased rectal temperature (1.3°C) and respiratory rate (38 breaths per minute) while it decreased dry matter intake (34%) and milk yield (32%). Plasma urea nitrogen (PUN) peaked following 3 d (46%) and milk urea nitrogen (MUN) peaked following 4 d of environmental treatment and while both decreased thereafter, PUN and MUN remained elevated compared with TN (PUN: 20%; MUN: 27%) on d 7 of HS. Contrary to expectations, calpain I and II abundance and activation and calpain activity were similar between groups. Likewise, relative protein abundance of E3 ligases, muscle atrophy F-box protein/atrogin-1 and muscle ring-finger protein-1, total ubiquitinated proteins, and proteasome activity were similar between environmental treatments. Finally, autophagosome degradation was also unaltered by HS. Counter to our hypothesis, these results suggest skeletal muscle proteolysis is not increased following 7 d of HS and call into question the presumed dogma that elevated skeletal muscle proteolysis, per se, drives increased AA mobilization.

Methane flux measurements along a floodplain soil moisture gradient in the Okavango Delta, Botswana.

Data-poor tropical wetlands constitute an important source of atmospheric CH4 in the world. We studied CH4 fluxes using closed chambers along a soil moisture gradient in a tropical seasonal swamp in the Okavango Delta, Botswana, the sixth largest tropical wetland in the world. The objective of the study was to assess net CH4 fluxes and controlling environmental factors in the Delta's seasonal floodplains. Net CH4 emissions from seasonal floodplains in the wetland were estimated at 0.072 ± 0.016 Tg a-1. Microbial CH4 oxidation of approximately 2.817 × 10-3 ± 0.307 × 10-3 Tg a-1 in adjacent dry soils of the occasional floodplains accounted for the sink of 4% of the total soil CH4 emissions from seasonal floodplains. The observed microbial CH4 sink in the Delta's dry soils is, therefore, comparable to the global average sink of 4-6%. Soil water content (SWC) and soil organic matter were the main environmental factors controlling CH4 fluxes in both the seasonal and occasional floodplains. The optimum SWC for soil CH4 emissions and oxidation in the Delta were estimated at 50% and 15%, respectively. Electrical conductivity and pH were poorly correlated (r2 ≤ 0.11, p < 0.05) with CH4 fluxes in the seasonal floodplain at Nxaraga. This article is part of a discussion meeting issue 'Rising methane: is warming feeding warming? (part1)'.

Molecular Differences in Skeletal Muscle After 1 Week of Active vs. Passive Recovery From High-Volume Resistance Training.

ABSTRACT: Vann, CG, Haun, CT, Osburn, SC, Romero, MA, Roberson, PA, Mumford, PW, Mobley, CB, Holmes, HM, Fox, CD, Young, KC, and Roberts, MD. Molecular differences in skeletal muscle after 1 week of active vs. passive recovery from high-volume resistance training. J Strength Cond Res 35(8): 2102-2113, 2021-Numerous studies have evaluated how deloading after resistance training (RT) affects strength and power outcomes. However, the molecular adaptations that occur after deload periods remain understudied. Trained, college-aged men (n = 30) performed 6 weeks of whole-body RT starting at 10 sets of 10 repetitions per exercise per week and finishing at 32 sets of 10 repetitions per exercise per week. After this period, subjects performed either active (AR; n = 16) or passive recovery (PR; n = 14) for 1 week where AR completed ∼15% of the week 6 training volume and PR ceased training. Variables related to body composition and recovery examined before RT (PRE), after 6 weeks of RT (POST), and after the 1-week recovery period (DL). Vastus lateralis (VL) muscle biopsies and blood samples were collected at each timepoint, and various biochemical and histological assays were performed. Group × time interactions (p < 0.05) existed for skeletal muscle myosin heavy chain (MHC)-IIa mRNA (AR > PR at POST and DL) and 20S proteasome activity (post-hoc tests revealed no significance in groups over time). Time effects (P < 0.05) existed for total mood disturbance and serum creatine kinase and mechano growth factor mRNA (POST > PRE &D L), VL pressure to pain threshold and MHC-IIx mRNA (PRE&DL > POST), Atrogin-1 and MuRF-1 mRNA (PRE < POST < DL), MHC-I mRNA (PRE < POST & DL), myostatin mRNA (PRE & POST < DL), and mechanistic target of rapamycin (PRE > POST & DL). No interactions or time effects were observed for barbell squat velocity, various hormones, histological metrics, polyubiquitinated proteins, or phosphorylated/pan protein levels of 4E-BP1, p70S6k, and AMPK. One week of AR after a high-volume training block instigates marginal molecular differences in skeletal muscle relative to PR. From a practical standpoint, however, both paradigms elicited largely similar responses.

Use of a Fluorescence-Based Assay To Measure Escherichia coli Membrane Potential Changes in High Throughput.

Bacterial membrane potential is difficult to measure using classical electrophysiology techniques due to the small cell size and the presence of the peptidoglycan cell wall. Instead, chemical probes are often used to study membrane potential changes under conditions of interest. Many of these probes are fluorescent molecules that accumulate in a charge-dependent manner, and the resulting fluorescence change can be analyzed via flow cytometry or using a fluorescence microplate reader. Although this technique works well in many Gram-positive bacteria, it generates fairly low signal-to-noise ratios in Gram-negative bacteria due to dye exclusion by the outer membrane. We detail an optimized workflow that uses the membrane potential probe, 3,3'-diethyloxacarbocyanine iodide [DiOC2(3)], to measure Escherichia coli membrane potential changes in high throughput and describe the assay conditions that generate significant signal-to-noise ratios to detect membrane potential changes using a fluorescence microplate reader. A valinomycin calibration curve demonstrates this approach can robustly report membrane potentials over at least an ∼144-mV range with an accuracy of ∼12 mV. As a proof of concept, we used this approach to characterize the effects of some commercially available small molecules known to elicit membrane potential changes in other systems, increasing the repertoire of compounds known to perturb E. coli membrane energetics. One compound, the eukaryotic Ca2+ channel blocker amlodipine, was found to alter E. coli membrane potential and decrease the MIC of kanamycin, further supporting the value of this screening approach. This detailed methodology permits studying E. coli membrane potential changes quickly and reliably at the population level.

The presence of two reduced function variants in CYP2C9 influences the acute response to glipizide.

AIMS: To examine whether the presence of two common missense variants in the CYP2C9 gene (rs1799853, encoding Arg144Cys and denoted as *2, and rs1057910, encoding Ile359Leu and denoted as *3) influences the acute physiological response to a single glipizide dose in individuals naïve to diabetes medications. METHODS: In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), 786 individuals genotyped for rs1799853/rs41291560 (*2) and rs1057910/rs9332214 (*3) were treated with 5 mg glipizide in the fasting state. Glucose and insulin levels were measured at baseline, 30, 60, 90, 120, 180 and 240 min for calculation of phenotypic endpoints of glipizide response. The challenge was aborted as a result of hypoglycaemia, defined as glucose <2.8 mmol/l or hypoglycaemia-related symptoms. RESULTS: Carriers with two reduced function alleles had a 50% larger insulin area under the curve than carriers with zero or one copy (P=0.037), although this finding was primarily driven by an individual with a robust insulin response. In adjusted analyses, the risk of aborting the glipizide challenge was doubled in two-copy carriers (P=0.034). No significant findings were observed in glucose-based endpoints. CONCLUSIONS: Carriers of two reduced function alleles in CYP2C9 may experience an increased insulin response to glipizide and be predisposed to a higher risk of hypoglycaemia, although no effect of genotype was seen in glucose-based measurements. Further studies are needed to clarify the utility of CYP2C9 genotyping to guide sulfonylurea treatment.

We are what we (think we) eat: The effect of expected satiety on subsequent calorie consumption.

Varying expected satiety (ES) for equi-calorie portions of different foods can affect subsequent feelings of hunger and fullness and alter consumption. To our knowledge, no study has manipulated ES for an equal portion of the same solid food, subsequent appetite has not been measured >3 h and studies have not consistently measured later consumption. Further, it is not clear whether any changes in hunger, fullness or later consumption that stem from differing ES are the result of a psychological or physiological response. The aims of this study were to manipulate ES for the same solid food on two occasions in order to compare participants' appetitive responses over a 4-h inter-meal period, to measure later consumption, and to assess whether any effect of ES on these measures was related to a physiological (i.e. total ghrelin) response. Using a within-subjects design, 26 healthy participants had their ES for omelettes manipulated experimentally, believing that a 3-egg omelette contained either 2 (small condition) or 4 (large condition) eggs. When ES was higher (large condition) participants ate significantly fewer calories at a lunchtime test meal (mean difference = 69 kcal [± 95% CI 4-136]) and consumed significantly fewer calories throughout the day (mean difference = 167 kcal [± 95% CI 26-309]). The results show that there was a significant main effect of time on hunger and fullness, but no main effect of 'portion size' (p > .05). There was also a significant interaction between time and portion size for hunger. There was no evidence for any significant differences in appetite or consumtpion resulting from changes in total ghrelin. Overall, the data suggest that ES for a solid food can be manipulated and that, when given at breakfast, having a higher ES for a meal significantly reduces lunchtime and whole day caloric consumption.

An International Laboratory Comparison Study of Volumetric and Gravimetric Hydrogen Adsorption Measurements.

In order to determine a material's hydrogen storage potential, capacity measurements must be robust, reproducible, and accurate. Commonly, research reports focus on the gravimetric capacity, and often times the volumetric capacity is not reported. Determining volumetric capacities is not as straight-forward, especially for amorphous materials. This is the first study to compare measurement reproducibility across laboratories for excess and total volumetric hydrogen sorption capacities based on the packing volume. The use of consistent measurement protocols, common analysis, and figure of merits for reporting data in this study, enable the comparison of the results for two different materials. Importantly, the results show good agreement for excess gravimetric capacities amongst the laboratories. Irreproducibility for excess and total volumetric capacities is attributed to real differences in the measured packing volume of the material.

Species-Specific (Hyalella azteca and Lymnea stagnalis) Dietary Accumulation of Gold Nano-particles Associated with Periphyton.

Ecological effects of gold nano-particles (AuNP) are examined due to growing use in consumer and industrial materials. This study investigated uptake and movement of AuNPs through an aquatic food chain. Simple (single-species) and diverse (multi-species) periphyton communities were exposed to AuNP (0, 100, 500 µg L-1 treatments). AuNP quickly aggregated and precipitated from the water column, suggesting it is an insignificant route of AuNP exposure even at elevated concentrations. Gold was measured in 100 and 500 µg L-1 periphyton treatments. Gold accumulation was similar between periphyton treatments, suggesting physical processes were important for AuNP basal accumulation. Hyalella azteca and Lymnea stagnalis whole body tissue analysis indicated gold accumulation may be attributed to different feeding mechanisms, general versus selective grazing, respectively. Results suggest trophic transfer of AuNP is organism specific and aggregation properties of AuNP are important when considering fate of nano-particles in the environment and movement through aquatic food webs.

Lichens or endophytes? The enigmatic genus Leptosillia in the Leptosilliaceae fam. nov. (Xylariales), and Furfurella gen. nov. (Delonicicolaceae).

Based on DNA sequence data, the genus Leptosillia is shown to belong to the Xylariales. Molecular phylogenetic analyses of ITS-LSU rDNA sequence data and of a combined matrix of SSU-ITS-LSU rDNA, rpb1, rpb2, tef1 and tub2 reveal that the genera Cresporhaphis and Liberomyces are congeneric with Leptosillia. Coelosphaeria fusariospora, Leptorhaphis acerina, Leptorhaphis quercus f. macrospora, Leptorhaphis pinicola, Leptorhaphis wienkampii, Liberomyces pistaciae, Sphaeria muelleri and Zignoëlla slaptonensis are combined in Leptosillia, and all of these taxa except for C. fusariospora, L. pinicola and L. pistaciae are epitypified. Coelosphaeria fusariospora and Cresporhaphis rhoina are lectotypified. Liberomyces macrosporus and L. saliciphilus, which were isolated as phloem and sapwood endophytes, are shown to be synonyms of Leptosillia macrospora and L. wienkampii, respectively. All species formerly placed in Cresporhaphis that are now transferred to Leptosillia are revealed to be non-lichenized. Based on morphology and ecology, Cresporhaphis chibaensis is synonymised with Rhaphidicyrtis trichosporella, and C. rhoina is considered to be unrelated to the genus Leptosillia, but its generic affinities cannot be resolved in lack of DNA sequence data. Phylogenetic analyses place Leptosillia as sister taxon to Delonicicolaceae, and based on morphological and ecological differences, the new family Leptosilliaceae is established. Furfurella, a new genus with the three new species, F. luteostiolata, F. nigrescens and F. stromatica, growing on dead branches of mediterranean fabaceous shrubs from tribe Genisteae, is revealed to be the closest relative of Delonicicola in the family Delonicicolaceae, which is emended. ITS rDNA sequence data retrieved from GenBank demonstrate that the Leptosilliaceae were frequently isolated or sequenced as endophytes from temperate to tropical regions, and show that the genus Leptosillia represents a widely distributed component of endophyte communities of woody plants.

Comparison of Digital Rectal Examination and Serum Prostate Specific Antigen in the Early Detection of Prostate Cancer: Results of a Multicenter Clinical Trial of 6,630 Men.

To compare the efficacy of digital rectal examination and serum prostate specific antigen (PSA) in the early detection of prostate cancer, we conducted a prospective clinical trial at 6 university centers of 6,630 male volunteers 50 years old or older who underwent PSA determination (Hybritech Tandom-E or Tandem-R assays) and digital rectal examination. Quadrant biopsies were performed if the PSA level was greater than 4 µg./l. or digital rectal examination was suspicious, even if transrectal ultrasonography revealed no areas suspicious for cancer. The results showed that 15% of the men had a PSA level of greater than 4 µg./l., 15% had a suspicious digital rectal examination and 26% had suspicious findings on either or both tests. Of 1,167 biopsies performed cancer was detected in 264. PSA detected significantly more tumors (82%, 216 of 264 cancers) than digital rectal examination (55%, 146 of 264, p = 0.001). The cancer detection rate was 3.2% for digital rectal examination, 4.6% for PSA and 5.8% for the 2 methods combined. Positive predictive value was 32% for PSA and 21% for digital rectal examination. Of 160 patients who underwent radical prostatectomy and pathological staging 114 (71%) had organ confined cancer: PSA detected 85 (75%) and digital rectal examination detected 64 (56%, p = 0.003). Use of the 2 methods in combination increased detection of organ confined disease by 78% (50 of 64 cases) over digital rectal examination alone. If the performance of a biopsy would have required suspicious transrectal ultrasonography findings, nearly 40% of the tumors would have been missed. We conclude that the use of PSA in conjunction with digital rectal examination enhances early prostate cancer detection. Prostatic biopsy should be considered if either the PSA level is greater than 4 µg./l. or digital rectal examination is suspicious for cancer, even in the absence of abnormal transrectal ultrasonography findings.

Dayside response of the magnetosphere to a small shock compression: Van Allen Probes, Magnetospheric MultiScale, and GOES-13.

Observations from Magnetospheric MultiScale (~8 Re) and Van Allen Probes (~5 and 4 Re) show that the initial dayside response to a small interplanetary shock is a double-peaked dawnward electric field, which is distinctly different from the usual bipolar (dawnward and then duskward) signature reported for large shocks. The associated E × B flow is radially inward. The shock compressed the magnetopause to inside 8 Re, as observed by Magnetospheric MultiScale (MMS), with a speed that is comparable to the E × B flow. The magnetopause speed and the E × B speeds were significantly less than the propagation speed of the pulse from MMS to the Van Allen Probes and GOES-13, which is consistent with the MHD fast mode. There were increased fluxes of energetic electrons up to several MeV. Signatures of drift echoes and response to ULF waves also were seen. These observations demonstrate that even very weak shocks can have significant impact on the radiation belts.

Wrong-site nerve blocks: 10 yr experience in a large multihospital health-care system.

INTRODUCTION: Although wrong-site surgery has garnered extensive scrutiny, the incidence of wrong-site blocks remains unknown. Our study thus sought to quantify the incidence of wrong-site blocks and examine some of their associated risk factors in our multihospital health-care system. METHODS: Using quality-improvement and billing data, we quantified the total number of blocks and wrong-site blocks occurring between July 1, 2002 and June 30, 2012 within the University of Pittsburgh Medical Center Health System. The incidence of wrong-site block was determined by block type, hospital, and type of service involved in performing the block. The incidence of wrong-site block was compared with that of wrong-site surgery. Fisher's exact tests were performed to determine associations between the incidence of wrong-site block and any of the aforementioned variables. A root-cause analysis was performed to determine the source of wrong-site blocks after the implementation of a timeout policy. RESULTS: Of the 85 915 patients receiving blocks, 70 441 received only unilateral blocks, yielding an overall incidence of wrong-site block of 1.28 (95% confidence interval 0.43-2.13) per 10 000 patients receiving unilateral blocks. The incidence of wrong-site block was highest with femoral blocks, and differed from the incidence of wrong-site surgery. All occurrences of wrong-site block after the implementation of the timeout policy involved policy violations. CONCLUSIONS: Our study provides the first incidence data on wrong-site block in a large patient population and can help hospitals to develop policies based on these data. It is yet to be determined whether active intervention can eliminate this adverse event.

Molecular markers for bladder cancer screening, early diagnosis, and surveillance: the WHO/ICUD consensus.

Due to the lack of disease-specific symptoms, diagnosis and follow-up of bladder cancer has remained a challenge to the urologic community. Cystoscopy, commonly accepted as a gold standard for the detection of bladder cancer, is invasive and relatively expensive, while urine cytology is of limited value specifically in low-grade disease. Over the last decades, numerous molecular assays for the diagnosis of urothelial cancer have been developed and investigated with regard to their clinical use. However, although all of these assays have been shown to have superior sensitivity as compared to urine cytology, none of them has been included in clinical guidelines. The key reason for this situation is that none of the assays has been included into clinical decision-making so far. We reviewed the current status and performance of modern molecular urine tests following systematic analysis of the value and limitations of commercially available assays. Despite considerable advances in recent years, the authors feel that at this stage the added value of molecular markers for the diagnosis of urothelial tumors has not yet been identified. Current data suggest that some of these markers may have the potential to play a role in screening and surveillance of bladder cancer. Well-designed protocols and prospective, controlled trials will be needed to provide the basis to determine whether integration of molecular markers into clinical decision-making will be of value in the future.

Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Myopathy is a poor prognostic feature in systemic sclerosis: results from the Canadian Scleroderma Research Group (CSRG) cohort.

OBJECTIVE: To determine the clinical impact of muscle involvement in a large systemic sclerosis (SSc) cohort. METHOD: Using the Canadian Scleroderma Research Group (CSRG) database, SSc patients with either elevated creatine kinase (CK) or a prior history of myositis/myopathy were identified. Regression and Kaplan-Meier analyses were performed to determine characteristics associated with muscle involvement in SSc and survival outcome. RESULTS: In 1145 patients with SSc, 5.6% had an elevated CK. This subset was more likely to be male (24.5% in elevated CK vs. 12.6% in normal CK, p < 0.013), younger (52 vs. 56 years, p < 0.045), have diffuse cutaneous SSc (dcSSc; 40.4% vs. 37.9%, p < 0.002), tendon friction rubs (30.0% vs. 13.4%, p < 0.001), and forced vital capacity (FVC) < 70% (23.9% vs. 13.1%, p < 0.039), be ribonucleoprotein (RNP) antibody positive (12.0% vs. 5.0%, p < 0.032), topoisomerase1 (topo1)-antibody positive (26.0% vs. 14.4%, p < 0.026), have a higher modified Rodnan skin score (MRSS; 16.14 vs. 9.81, p < 0.001), and a higher Health Assessment Questionnaire (HAQ) score (0.98 vs. 0.79, p < 0.011). Survival was reduced for patients with elevated CK (p < 0.025). Nearly 10% of patients in the CSRG cohort had a prior history of myositis/myopathy. This subset also had findings similar to those with elevated CK and increased mortality (p < 0.003). CONCLUSIONS: Muscle involvement in SSc has a poor prognosis impacting survival, especially in men with early dcSSc with topo1 and RNP autoantibodies and interstitial lung disease (ILD).

Pilot study of modified LMB-based therapy for children with ataxia-telangiectasia and advanced stage high grade mature B-cell malignancies.

Children with ataxia-telangiectasia (A-T) and cancer have a poorer prognosis due in part to increased treatment-related toxicity. We piloted a curative intent approach in five children with A-T who presented with advanced stage (III, n = 2; IV, n = 3) B-NHL (diffuse large B-cell lymphoma, n = 4; Burkitt leukemia, n = 1) using a modified LMB-based protocol. Two achieved sustained CCR (one, CCR at 6 years; one, pulmonary death after 3 years in CCR). Two died from toxicity during induction and 1 failed induction with progressive disease. Novel therapeutic approaches which overcome drug resistance and are less toxic are needed for children with A-T and B-NHL.

Bone mineral density among long-term survivors of childhood acute lymphoblastic leukemia: results from the St. Jude Lifetime Cohort Study.

BACKGROUND: The prevalence of low bone mineral density (BMD) in adult survivors of childhood acute lymphoblastic leukemia (ALL), and the degree of recovery or decline, are not well elucidated. PROCEDURE: Study subjects (age ≥ 18 years and ≥10 years post-diagnosis) participated in an institutional follow-up protocol and risk-based clinical evaluation based on Children's Oncology Group guidelines. Trabecular volumetric BMD was ascertained using quantitative computed tomography, reported as age- and sex-specific Z-scores. RESULTS: At median age 31 years, 5.7% of 845 subjects had a BMD Z-score of ≤-2 and 23.8% had a Z-score of -1 to -2. Cranial radiation dose of ≥24 Gy, but not cumulative methotrexate or prednisone equivalence doses, was associated with a twofold elevated risk of a BMD Z-score of ≤-1. The cranial radiation effect was stronger in females than in males. In a subset of 400 subjects, 67% of those who previously had a BMD Z-score of ≤-2 improved by one or more categories a median of 8.5 years later. CONCLUSIONS: Very low BMD was relatively uncommon in this sample of adult survivors of childhood ALL, and BMD Z-scores tended to improve from adolescence to young adulthood. High-dose cranial or craniospinal radiation exposure was the primary predictor of suboptimal BMD in our study. Given that cranial radiation treatment for childhood ALL is used far more sparingly now than in earlier treatment eras, concerns about persistently low BMD among most current childhood ALL patients may be unwarranted.

Calcium and cholecalciferol supplementation provides no added benefit to nutritional counseling to improve bone mineral density in survivors of childhood acute lymphoblastic leukemia (ALL).

BACKGROUND: We sought to improve lumbar spine bone mineral density (LS-BMD) in long-term survivors of childhood acute lymphoblastic leukemia (ALL) using calcium and cholecalciferol supplementation. PROCEDURE: This double-blind, placebo-controlled trial randomized 275 participants (median age, 17 [9-36.1] years) with age- and gender-specific LS-BMD Z-scores <0 to receive nutritional counseling with supplementation of 1,000 mg/day calcium and 800 International Unit cholecalciferol or placebo for 2 years. The primary outcome was change in LS-BMD assessed by quantitative computerized tomography (QCT) at 24 months. Linear regression models were employed to identify the baseline risk factors for low LS-BMD and to compare LS-BMD outcomes. RESULTS: Pre-randomization LS-BMD below the mean was associated with male gender (P = 0.0024), White race (P = 0.0003), lower body mass index (P < 0.0001), and cumulative glucocorticoid doses of ≥ 5,000 mg (P = 0.0012). One hundred eighty-eight (68%) participants completed the study; 77% adhered to the intervention. Mean LS-BMD change did not differ between survivors randomized to supplements (0.33 ± 0.57) or placebo (0.28 ± 0.56). Participants aged 9-13 years and those 22-35 years had the greatest mean increases in LS-BMD (0.50 ± 0.66 and 0.37 ± 0.23, respectively). Vitamin D insufficiency (serum 25[OH]D <30 ng/ml) found in 296 (75%), was not associated with LS-BMD outcomes (P = 0.78). CONCLUSION: Cholecalciferol and calcium supplementation provides no added benefit to nutritional counseling for improving LS-BMD among adolescent and young adult survivors of ALL (93% of whom had LS-BMD Z-scores above the mean at study entry).