Influence of fiber degradability of corn silage in diets with lower and higher fiber content on lactational performance, nutrient digestibility, and ruminal characteristics in lactating Holstein cows.

The effect of neutral detergent fiber (NDF) degradability of corn silage in diets containing lower and higher NDF concentrations on lactational performance, nutrient digestibility, and ruminal characteristics in lactating Holstein cows was measured. Eight ruminally cannulated Holstein cows averaging 91 ± 4 (standard error) days in milk were used in a replicated 4 × 4 Latin square design with 21-d periods (7-d collection periods). Dietary treatments were formulated to contain either conventional (CON; 48.6% 24-h NDF degradability; NDFD) or brown midrib-3 (BM3; 61.1% 24-h NDFD) corn silage and either lower NDF (LNDF) or higher NDF (HNDF) concentration (32.0 and 35.8% of ration dry matter, DM) by adjusting the dietary forage content (52 and 67% forage, DM basis). The dietary treatments were (1) CON-LNDF, (2) CON-HNDF, (3) BM3-LNDF, and (4) BM3-HNDF. Data were analyzed as a factorial arrangement of diets within a replicated Latin square design with the MIXED procedure of SAS (SAS Institute Inc., Cary, NC) with fixed effects of NDFD, NDF, NDFD × NDF, period(square), and square. Cow within square was the random effect. Time and its interactions with NDFD and NDF were included in the model when appropriate. An interaction between NDFD and NDF content resulted in the HNDF diet decreasing dry matter intake (DMI) with CON corn silage but not with BM3 silage. Cows fed the BM3 corn silage had higher DMI than cows fed the CON corn silage, whereas cows fed the HNDF diet consumed less DM than cows fed the LNDF diet. Cows fed the BM3 diets had greater energy-corrected milk yield, higher milk true protein content, and lower milk urea nitrogen concentration than cows fed CON diets. Additionally, cows fed the BM3 diets had greater total-tract digestibility of organic matter and NDF than cows fed the CON diets. Compared with CON diets, the BMR diets accelerated ruminal NDF turnover. When incorporated into higher NDF diets, corn silage with greater in vitro 24-h NDFD and lower undegradable NDF at 240 h of in vitro fermentation (uNDF240) allowed for greater DMI intake than CON. In contrast, for lower NDF diets, NDFD of corn silage did not affect DMI, which suggests that a threshold level of inclusion of higher NDFD corn silage is necessary to observe enhanced lactational performance. Results suggest that there is a maximum gut fill of dietary uNDF240 and that higher NDFD corn silage can be fed at greater dietary concentrations.

Evaluation of source of corn silage and trace minerals on rumen characteristics and passage rate of Holstein cows.

The effects of source of corn silage and trace mineral on rumen fermentation, turnover, and particle passage rates were evaluated with 8 ruminally cannulated Holstein cows averaging 83 (standard error = 5) days in milk in a replicated 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments and 28-d periods. The diets consisted (dry basis) of 55% conventional (CON) or brown midrib-3 (BM3) corn silage, 2% chopped wheat straw, and 43% grain mix with either sulfate (STM) or hydroxy (HTM) source of Cu, Zn, and Mn trace minerals. The targeted supplemental amount of Cu, Zn, and Mn was 194, 1,657, and 687 mg/d, respectively. The dietary treatments were (1) CON-STM, (2) CON-HTM, (3) BM3-STM, and (4) BM3-HTM. Dietary nutrient composition of BM3 diets averaged 32.1% amylase neutral detergent fiber on an organic matter basis (aNDFom) and 6.9% undigested neutral detergent fiber at 240 h of in vitro fermentation (uNDF240om; % of dry matter), and CON diets averaged 36.2% aNDFom and 8.6% uNDF240om (% of dry matter). Data were summarized by period and analyzed as a replicated Latin square design with fixed model effects for corn silage, trace mineral, corn silage and trace mineral interaction, period within replicated square, and replicated square using the MIXED procedure of SAS (version 9.4, SAS Institute Inc., Cary, NC). Cow within replicate was a random effect. Daily mean, standard deviation, minimum, and maximum for rumen pH were unaffected by corn silage or trace mineral source. Cows fed the CON diets had greater rumen acetate percentage than cows fed the BM3 diets (65.7 vs. 64.7 molar %). In contrast, cows fed the BM3 diets had greater rumen propionate percentage than cows fed the CON diets (21.4 vs. 20.4 molar %). Total volatile fatty acid concentration was lower for cows fed STM versus HTM in BM3 diets, but not for the cows fed the CON diets. Cows fed the BM3 diets had faster turnover rate and shorter turnover time for uNDF240om than cows fed the CON diets (3.12 vs. 2.86%/h and 33.3 vs. 36.5 h, respectively). Cows fed the BM3 diets had a faster passage rate of small and medium corn silage neutral detergent fiber particles than cows fed the CON diets (5.73 vs. 5.37%/h and 4.74 vs. 4.31%/h, respectively). We observed a corn silage by source of trace mineral interaction on organic matter and uNDF240om rumen pool size and organic matter turnover. Overall, source of corn silage had a pronounced influence on rumen dynamics presumably related to greater in vitro neutral detergent fiber digestibility and lower uNDF240om content of BM3 corn silage that allowed for faster turnover of indigestible neutral detergent fiber and greater passage rate of corn silage particles. In contrast, the source of trace mineral had much less significant effects on rumen fermentation, turnover, and particle passage rates. Corn silage-based diets intended to enhance rumen fiber fermentation, turnover, and passage are more affected by source and digestibility of neutral detergent fiber than source of dietary trace minerals.

Evaluation of source of corn silage and trace minerals on lactational performance and total-tract nutrient digestibility in Holstein cows.

We evaluated the effects of source of corn silage and trace minerals on lactational performance and total-tract digestibility (TTD) of nutrients in 16 Holstein cows averaging 82 (standard error = 3) days in milk in a replicated 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments with 28-d periods. The diets consisted [dry matter (DM) basis] of 55% conventional (CON) or brown midrib-3 (BM3) corn silage, 2% chopped wheat straw, and 43% grain mix with either sulfate (STM) or hydroxy (HTM) sources of copper, manganese, and zinc trace minerals. The targeted supplemental concentrations of copper, zinc, and manganese were 194, 1,657, and 687 mg/d, respectively. The dietary treatments were CON-STM, CON-HTM, BM3-STM, and BM3-HTM. The dietary nutrient composition of the BM3 diets averaged 32.1% amylase neutral detergent fiber on an organic matter basis (aNDFom) and 6.9% undigested neutral detergent fiber at 240 h (uNDF240om; % of DM), and CON diets averaged 36.2% aNDFom and 8.6% uNDF240om (% of DM). The average supplemental concentrations of copper, zinc, and manganese for the STM diets were 10, 41, and 64 mg/kg, respectively, and the average supplemental concentrations of copper, zinc, and manganese for the HTM diets were 10, 40, and 62 mg/kg, respectively. The average total dietary concentrations of copper, zinc, and manganese for the STM diets were 17, 104, and 60 mg/kg, respectively, and the average total dietary concentrations of copper, zinc, and manganese for the HTM diets were 17, 91, and 66 mg/kg, respectively. Data were summarized by period and analyzed as a replicated Latin square design with fixed model effects for corn silage, trace minerals, corn silage × trace mineral interaction, period within replicated square, and replicated square using the MIXED procedure of SAS. Cow within replicated square was a random effect. Cows fed the BM3 diets had greater dry matter intake (DMI) and milk yield (28.1 and 47.0 kg/d) than cows fed the CON diets (27.5 and 44.7 kg/d). We found no significant interaction between corn silage and trace minerals for DMI and milk yield. Cows fed the HTM diets (28.1 kg/d) had a greater DMI than cows fed the STM diets (27.5 kg/d). Cows fed the BM3 diets had greater TTD of DM and OM (72.8 and 74.1% of DM) than cows fed the CON diets (71.1 and 72.3% of DM). Cows fed the HTM diets had a tendency for greater TTD of aNDFom than cows fed the STM diets (56.8 vs. 54.9% of DM). Cows fed the CON diets ruminated longer during the day than cows fed the BM3 diets (524 vs. 496 min/d). Corn silage with greater NDF digestibility and lower uNDF240om enhanced DMI, milk yield, and TTD of DM and OM, and hydroxy trace minerals improved DMI and tended to improve TTD of aNDFom. The source of corn silage and trace minerals should be taken into consideration when formulating diets for high-producing dairy cows.

A systematic review of community-based interventions for the treatment of adolescents with overweight and obesity.

Adolescent obesity is a risk factor for obesity and other chronic disease in adulthood. Evidence for the effectiveness of community-based obesity treatment programs for adolescents is required to inform policy and clinical decisions. This systematic review aims to evaluate recent effective and scalable community-based weight management programs for adolescents (13-17 years) who are overweight or obese. Eight databases (Medline, Embase, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Informit, and Scopus) were searched for studies published between January 2011-2 March 2017 which are scalable in a community setting and reported primary outcome measures relating to weight. Following deduplication, 10,074 records were screened by title/abstract with 31 publications describing 21 programs included in this review. Programs were heterogeneous in nature (including length, number and frequency of sessions, parent-involvement and technology involvement). Reduction in adolescent BMIz ranged from 2 to 9% post-program and from 2 to 11% after varied lengths of follow-up. Study quality varied (n = 5 weak; n = 8 moderate; n = 8 high), and findings are limited by the risk of selection and retention bias in the included studies. Factors including the effectiveness and acceptability to the target population must be considered when selecting such community programs.

Nonstructural protein 5A resistance profile in patients with chronic hepatitis C treated with ledipasvir-containing regimens without sofosbuvir.

The study aimed to evaluate the effects of baseline hepatitis C virus (HCV) nonstructural protein 5A (NS5A) resistance-associated substitutions (RASs) on sustained virologic response to ledipasvir (LDV)-containing regimens in the absence of sofosbuvir (SOF) in patients with HCV genotype (GT) 1 infection across 6 phase 2 clinical studies. We analysed data from 1103 patients who received either LDV + vedroprevir (NS3 protease inhibitor) + tegobuvir (NS5B inhibitor) ± ribavirin or LDV + ribavirin + pegylated interferon. Population sequencing of HCV NS5A was performed at baseline and at virologic failure from patient plasma samples. Of 1045 patients with available baseline sequences, 747 (67.7%) had GT1a, and 298 (26.9%) had GT1b infection. The overall prevalence of NS5A RASs at baseline was 9.4%; 7.6% (57/747) and 13.8% (41/298) of patients with GT1a and GT1b infection, respectively. The majority of GT1a-infected patients with NS5A RASs at baseline had a single NS5A RAS (78.9%) at NS5A positions K24R, M28T, Q30H/L, L31M and Y93H/N/C/S. The spectrum of NS5A RASs detected in GT1b patients was much less diverse compared to GT1a patients, with all patients harbouring a single NS5A RAS either L31M or Y93H/C. For patients treated with LDV-containing regimens in the absence of SOF, the presence of baseline NS5A RASs was associated with low SVR rates. In patients with virologic failure, nearly all had either pre-existing and/or emergent NS5A RASs: 287/287 (100%) and 40/42 (95.2%) patients with GT1a and GT1b infection, respectively. Three novel NS5A substitutions were identified as emergent NS5A RASs: K26E and S38F in GT1a; and L31I in GT1b. In conclusion, the presence of NS5A RASs at baseline reduced the SVR rate in patients treated with LDV in combination vedroprevir + tegobuvir ± ribavirin or ribavirin + pegylated interferon. Virologic failure was associated with the detection of NS5A RASs in nearly all patients. These results suggest that the resistance barrier may differ depending on HCV drug combination and may be more important than that of the individual DAAs.

Intrapatient viral diversity and treatment outcome in patients with genotype 3a hepatitis C virus infection on sofosbuvir-containing regimens.

Treatment with the direct-acting antiviral agent (DAA) sofosbuvir (SOF), an NS5B inhibitor, and velpatasvir (VEL), an NS5A inhibitor, demonstrates viral cure rates of ≥95% in hepatitis C virus (HCV) genotypes (GT) 1-6. Here, we investigated intrapatient HCV diversity in NS5A and NS5B using Shannon entropy to examine the relationship between viral diversity and treatment outcome. At baseline, HCV diversity was lowest in patients infected with HCV GT3 as compared to the other GTs, and viral diversity was greater in NS5A than NS5B (P < .0001). Treatment outcome with SOF/VEL or the comparator regimen of SOF with ribavirin (RBV) was not correlated with baseline diversity. However, among persons treated with SOF/VEL, a decrease in diversity from baseline was observed at relapse in the majority virologic failures, consistent with a viral bottleneck event at relapse. In contrast, an increase in diversity was observed in 27% of SOF+RBV virologic failures. We investigated whether the increase in diversity was due to an increase in the transition rate, one mode of potential RBV-mediated mutagenesis; however, we found no evidence of this mechanism. Overall, we did not observe that viral diversity at baseline influenced treatment outcome, but the diversity changes observed at relapse can improve our understanding of RBV viral suppression in vivo.

Resistance characterization of ledipasvir and velpatasvir in hepatitis C virus genotype 4.

HCV genotype 4 (GT4) has often been overlooked in drug development, even though it infects ~20 million people worldwide. Ledipasvir/sofosbuvir and sofosbuvir/velpatasvir were highly efficacious in GT4 HCV-infected patients from GS-US-337-1119 and GS-US-342-1138. Here, we characterize the resistance profile of ledipasvir (LDV) and velpatasvir (VEL) in patients with GT4 HCV infection. NS5A deep-sequencing was performed for 454 patients infected with HCV GT4 at baseline, including 44 patients enrolled in GS-US-337-1119 and 116 patients enrolled in GS-US-342-1138, and at relapse for patients with virologic failure. LDV and VEL susceptibilities of 56 patient isolates were determined. In GS-US-337-1119, SVR12 rates were 100% for all subtypes except 4b and 4r. Phenotypic assessment of 56 HCV NS5A patient isolates from various GT4 subtypes indicated that LDV had high potency for the common subtypes 4a/d, and subtypes 4c/f/k/l/m/n/o/p/r/t despite the presence of resistance-associated substitutions (RASs). For the rare GT4b, LDV median EC50 was higher, but with a broad range of individual values. Importantly, all GT4b isolates tested had 2-4 NS5A RASs, some including Y93H. Similarly, the 2 GT4r infected patients who had virologic relapse had rare triple RASs. Reversion of these substitutions to the consensus residue significantly increased LDV susceptibility. In GS-US-342-1138, all patients achieved SVR12, regardless of their subtype or presence of RASs. In vitro data confirmed that VEL is potent against all GT4 isolates tested. LDV and VEL are potent antiviral drugs, estimated to be effective against >95% and >99%, respectively, of GT4 HCV isolates.

Effects of rotating antibiotic and ionophore feed additives on volatile fatty acid production, potential for methane production, and microbial populations of steers consuming a moderate-forage diet.

Ionophores and antibiotics have been shown to decrease ruminal methanogenesis both in vitro and in vivo but have shown little evidence toward a sustainable means of mitigation. Feed additive rotation was proposed and investigated for methane, VFA, and microbial population response. In the present study, cannulated steers ( = 12) were fed a moderate-forage basal diet in a Calan gate facility for 13 wk. In addition to the basal diet, steers were randomly assigned to 1 of 6 treatments: 1) control, no additive; 2) bambermycin, 20 mg bambermycin/d; 3) monensin, 200 mg monensin/d; 4) the basal diet + weekly rotation of bambermycin and monensin treatments (B7M); 5) the basal diet + rotation of bambermycin and monensin treatments every 14 d (B14M); and 6) the basal diet + rotation of bambermycin and monensin treatments every 21 d (B21M). Steers were blocked by weight in a randomized complete block design where the week was the repeated measure. Rumen fluid was collected weekly for analysis ( = 13), and results were normalized according to individual OM intake (OMI; kg/d). Potential activity of methane production was not significantly different among treatments ( > 0.05). However, treatment tended to affect the CH-to-propionate ratio ( = 0.0565), which was highest in the control and lowest in the monensin, B21M, and B14M treatments (0.42 vs. 0.36, 0.36, and 0.33, respectively). The CH:propionate ratio was lowest in wk 2 and 3 ( < 0.05) but the ratio in wk 4 to 12 was not different from the ratio in wk 0. Week also affected total VFA, with total VFA peaking at wk 3 and plummeting at wk 4 (4.02 vs. 2.86 m/kg OMI; < 0.05). A significant treatment × week interaction was observed for the acetate-to-propionate (A:P) ratio, where bambermycin- and rotationally fed steers did not have a reduced A:P ratio compared with monensin-fed steers throughout the feeding period ( < 0.0001). Microbial analysis revealed significant shifts, but several predominant classes showed adaptation between 4 and 6 wk after additive initiation. There was no significant evidence to suggest that rotations of monensin and bambermycin provided additional benefits to steers consuming a moderate-forage diet at the microbial/animal and environmental level versus those continuously fed.

No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic hepatitis B after 8 years of treatment.

A major hurdle in the long-term treatment of chronic hepatitis B (CHB) patients is to maintain viral suppression in the absence of drug resistance. To date, no evidence of resistance to tenofovir disoproxil fumarate (TDF) has been observed. A cumulative evaluation of CHB patients who qualified for resistance surveillance over 8 years of TDF treatment was conducted. Patients in studies GS-US-174-0102 (HBeAg-) and GS-US-174-0103 (HBeAg+) were randomized 2:1 to receive TDF or adefovir dipivoxil (ADV) for 48 weeks followed by open-label TDF through year 8. Population sequencing of HBV pol/RT was attempted for all TDF-treated patients at baseline and, annually if viremic, at discontinuation, or with addition of emtricitabine. Overall, 88/641 (13.7%) patients qualified for sequence analysis at one or more time points. The percentage of patients qualifying for sequence analysis declined over time, from 9 to 11% in years 1-2 to <4% over years 3-8. Forty-one episodes of virologic breakthrough (VB) occurred throughout the study, with most (n=29, 70%) associated with nonadherence to study medication. Fifty-nine per cent of VB patients with an opportunity to resuppress HBV achieved HBV DNA resuppression. A minority of patients who qualified for sequencing had polymorphic (41/165, 24.8%) or conserved (17/165, 10.3%) site changes in pol/RT, with six patients developing lamivudine and/or ADV resistance-associated mutations. No accumulation of conserved site changes was detected. The long-term treatment of CHB with TDF monotherapy maintains effective suppression of HBV DNA through 8 years, with no evidence of TDF resistance or accumulation of conserved site changes.

Resistance Analyses of Japanese Hepatitis C-Infected Patients Receiving Sofosbuvir or Ledipasvir/Sofosbuvir Containing Regimens in Phase 3 Studies.

High rates of sustained virologic response (SVR) has been achieved in Japanese patients with chronic hepatitis C virus (HCV) genotype (GT)1 and GT2 infection treated with ledipasvir/sofosbuvir (LDV/SOF) ±ribavirin (RBV) and SOF+RBV, respectively. We evaluated the effect of baseline HCV NS5A and NS5B resistance-associated variants (RAVs) on treatment outcome and characterized variants at virologic failure. Baseline deep sequencing for NS5A and NS5B genes was performed for all GT1 patients. Deep sequencing of NS5A (GT1 only) and NS5B (GT1 and GT2) was performed for patients who failed treatment or discontinued early with detectable HCV RNA (i.e., >25 IU/mL). In patients with HCV GT1 infection, 22.3% (GT1a: 2/11; GT1b: 74/330) had ≥1 baseline NS5A RAV. The most frequent NS5A RAVs in GT1b were Y93H (17.9%, 59/330) and L31M (2.4%, 8/330). Despite the presence of NS5A RAVs at baseline, 100% and 97% of patients achieved SVR12, compared with 100% and 99% for those with no NS5A RAVs with LDV/SOF and LDV/SOF+RBV, respectively. All patients with NS5B RAVs at baseline achieved SVR12. Of the 153 patients with GT2 infection (GT2a 60.1%, GT2b 39.9%), 3.3% (5/153) experienced viral relapse. No S282T or other NS5B RAVs were detected at baseline or relapse; no change in susceptibility to SOF or RBV was observed at relapse. In conclusion, LDV/SOF and SOF+RBV demonstrate a high barrier to resistance in Japanese patients with HCV GT1 and GT2 infection. The presence of baseline NS5A RAVs did not impact treatment outcome in GT1 Japanese patients treated with LDV/SOF for 12 weeks.

Antiviral response and resistance analysis of treatment-naïve HCV-infected patients receiving single and multiple doses of GS-9190.

GS-9190 is a NS5B non-nucleoside analogue with demonstrated effectiveness in a Phase 1 monotherapy study and in combination with other DAAs for treatment of chronic HCV infection. Here, the resistance profile of GS-9190 monotherapy in a Phase 1b study was investigated. Resistance analysis was performed by population sequencing and allele-specific PCR (AS-PCR) for Y448H with an assay cut-off of 0.5%. Phenotypic susceptibility analyses were performed on patient isolates as well as site-directed mutagenesis of mutations selected during monotherapy. No resistance-associated variants were observed in patients before or after receiving single doses of GS-9190 by population sequencing. In contrast, in patients who received GS-9190 for 8 days, mutations Y448H and Y452H in NS5B were observed by population sequencing in 21/36 (58%) and 2/36 (5.6%) patients, respectively, at Day 8 or Day 14. Among the remaining 15 patients who had no detectable Y448H at Day 8 or Day 14 by population sequencing, low frequencies of Y448H ranging from 1.3 to 9.7% were detected in 14 of 15 patients by AS-PCR. By AS-PCR, Y448H remained detectable at reduced frequency in the majority of patients analysed through 4-6 months of follow-up. Chimeric HCV replicons constructed with the NS5B sequence from patients with Y448H and Y448H + Y452H/Y demonstrated 27-fold and 78.5-fold reduced susceptibility to GS-9190. In conclusion, Y448H was rapidly selected in the majority of patients receiving multiple doses of GS-9190 as monotherapy, despite undetectable levels in pretreatment samples. Y448H confers reduced susceptibility to GS-9190 and other NNIs and persisted in most patients for months post-treatment.

Estimating energy expenditure in vascular surgery patients: Are predictive equations accurate enough?

BACKGROUND & AIMS: Malnutrition is prevalent in vascular surgical patients who commonly seek tertiary care at advanced stages of disease. Adjunct nutrition support is therefore pertinent to optimise patient outcomes. To negate consequences related to excessive or suboptimal dietary energy intake, it is essential to accurately determine energy expenditure and subsequent requirements. This study aims to compare resting energy expenditure (REE) measured by indirect calorimetry, a commonly used comparator, to REE estimated by predictive equations (Schofield, Harris-Benedict equations and Miller equation) to determine the most suitable equation for vascular surgery patients. METHODS: Data were collected from four studies that measured REE in 77 vascular surgery patients. Bland-Altman analyses were conducted to explore agreement. Presence of fixed or proportional bias was assessed by linear regression analyses. RESULTS: In comparison to measured REE, on average REE was overestimated when Schofield (+857 kJ/day), Harris-Benedict (+801 kJ/day) and Miller (+71 kJ/day) equations were used. Wide limits of agreement led to an over or underestimation from 1552 to 1755 kJ. Proportional bias was absent in Schofield (R2 = 0.005, p = 0.54) and Harris-Benedict equations (R2 = 0.045, p = 0.06) but was present in the Miller equation (R2 = 0.210, p < 0.01) even after logarithmic transformation (R2 = 0.213, p < 0.01). CONCLUSIONS: Whilst the Miller equation tended to overestimate resting energy expenditure and was affected by proportional bias, the limits of agreement and mean bias were smaller compared to Schofield and Harris-Benedict equations. This suggested that it is the preferred predictive equation for vascular surgery patients. Future research to refine the Miller equation to improve its overall accuracy will better inform the provision of nutritional support for vascular surgery patients and subsequently improve outcomes. Alternatively, an equation might be developed specifically for use with vascular surgery patients.

Evolution of the HCV viral population from a patient with S282T detected at relapse after sofosbuvir monotherapy.

Clinical phase II/III studies of the nucleotide analogue HCV NS5B inhibitor sofosbuvir (SOF) have demonstrated high efficacy in HCV-infected patients in combination therapy. To date, resistance to SOF (S282T in NS5B) has rarely been detected in patients. In this study, we investigated the evolution of S282T viral variants detected in one HCV genotype 2b-infected patient who relapsed following 12 weeks of SOF monotherapy. Deep sequencing of the NS5B gene was performed on longitudinal plasma samples at baseline, days 2 and 3 on SOF, and longitudinal samples post-SOF treatment through week 48. Intrapatient HCV evolution was analysed by maximum-likelihood phylogenetic analysis. Deep sequencing analysis revealed a low level pre-existence of S282T at 0.05% of viral sequences (4/7755 reads) at baseline and 0.03% (6/23 415 reads) at day 2 on SOF. Viral relapse was detected at week 4 post-treatment where 99.8% of the viral population harboured S282T. Follow-up analysis determined that S282T levels diminished post-treatment reaching undetectable levels 24-48 weeks post-SOF. Phylogenetic analysis together with the persistence of unique post-treatment mutations in all post-SOF samples suggested that growth of wild type resulted from reversion of the S282T mutant to a wild type and not outgrowth of the baseline wild-type population. Our data suggest that a very low level of pre-existing S282T at baseline in this patient was enriched and transiently detected following SOF monotherapy. Despite relapse with drug resistance to SOF, this patient was successfully retreated with SOF plus ribavirin for 12 weeks and is now cured from HCV infection.

The impact of abdominal aortic aneurysm on muscle mass and energy expenditure: A novel preliminary investigation.

OBJECTIVE: Vascular surgical patients, including those with abdominal aortic aneurysm (AAA), are nutritionally vulnerable. The aim of this study was to compare resting energy expenditure (REE) of patients with AAA relative to age- and gender-matched controls and explore relationships between aneurysm size and muscle mass. METHODS: Twenty patients with AAA underwent assessment of REE using indirect calorimetry. Mid-arm circumference and triceps skinfold thickness were measured and corrected arm muscle area calculated. Twenty gender- and age-matched controls were assessed using the same procedures. RESULTS: Mean (SD) age of participants with AAA was 74.7 (7.7) years, size of AAA ranged from 45 to 70 mm. Median (IQR) REE was significantly higher than controls [5990 (5469, 7017) kJ/day versus 5086 (4536, 5886) kJ/day, p = .011; or 69 (64, 80) kJ/kg/day versus 66 (61, 69) kJ/kg/day, p = .046]. While weight-adjusted REE was independent of aneurysm size (r = .200; p = .397), as aneurysm size increased, weight-adjusted corrected arm muscle area decreased (r = -.576; p = .008). CONCLUSION: The raised REE and decline in muscle mass associated with larger AAA suggest that early detection and attention to nutritional requirements of patients with AAA may be warranted.

Acute gastrointestinal illness following a prolonged community-wide water emergency.

The drinking water infrastructure in the United States is ageing; extreme weather events place additional stress on water systems that can lead to interruptions in the delivery of safe drinking water. We investigated the association between household exposures to water service problems and acute gastrointestinal illness (AGI) and acute respiratory illness (ARI) in Alabama communities that experienced a freeze-related community-wide water emergency. Following the water emergency, investigators conducted a household survey. Logistic regression models were used to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for self-reported AGI and ARI by water exposures. AGI was higher in households that lost water service for ⩾7 days (aPR 2·4, 95% CI 1·1-5·2) and experienced low water pressure for ⩾7 days (aPR 3·6, 95% CI 1·4-9·0) compared to households that experienced normal service and pressure; prevalence of AGI increased with increasing duration of water service interruptions. Investments in the ageing drinking water infrastructure are needed to prevent future low-pressure events and to maintain uninterrupted access to the fundamental public health protection provided by safe water supplies. Households and communities need to increase their awareness of and preparedness for water emergencies to mitigate adverse health impacts.

A randomised controlled trial of supervised exercise regimens and their impact on walking performance, skeletal muscle mass and calpain activity in patients with intermittent claudication.

OBJECTIVES: Supervised exercise training (SET) is recommended for patients with intermittent claudication (IC). The optimal exercise programme has not been identified, and the potential adverse effects of exercise on these patients warrant consideration. Calpain proteases have been linked with tissue atrophy following ischaemia-reperfusion injury. High calpain activity may therefore cause muscle wasting in claudicants undergoing SET, and skeletal muscle mass (SMM) is integral to healthy ageing. This study assesses the impact of (1) treadmill-based SET alone; and (2) treadmill-based SET combined with resistance training on pain-free walking distance (PFWD), SMM, and calpain activity. METHODS: Thirty-five patients with IC were randomised to 12 weeks of treadmill only SET (group A), or combined treadmill and lower-limb resistance SET (group B). PFWD via a 6-minute walking test, SMM via dual energy X-ray absorptiometry, and calpain activity via biopsies of gastrocnemius muscles were analysed. RESULTS: Intention-to-treat analyses revealed PFWD improved within group A (160 m to 204 m, p = .03), but not group B (181 m to 188 m, p = .82). There was no between group difference (p = .42). Calpain activity increased within group A (1.62 × 10(5) fluorescent units [FU] to 2.21 × 10(5) FU, p = .05), but not group B. There was no between group difference (p = .09). SMM decreased within group A (-250 g, p = .11) and increased in group B (210 g, p = .38) (p = .10 between groups). Similar trends were evident for per protocol analyses, but, additionally, change in SMM was significantly different between groups (p = .04). CONCLUSIONS: Neither exercise regimen was superior in terms of walking performance. Further work is required to investigate the impact of the calpain system on SMM in claudicants undertaking SET.

Information needs of cancer patients and survivors regarding diet, exercise and weight management: a qualitative study.

While advanced cancer is often associated with weight loss, curative cancer treatment is often associated with weight gain. Weight gain during treatment may be associated with greater risk of cancer recurrence and development of lifestyle diseases. Currently, limited resources are available to cancer patients focussed on weight control. This study assessed the information needs of patients undergoing curative chemotherapy regarding diet, exercise and weight management for the purpose of developing weight management resources. Focus groups were held with oncology practitioners, patients and survivors to determine current information provision and needs. Focus groups highlighted a perception that information provision regarding diet, exercise and weight management is insufficient and no routine assessment of weight occurs during chemotherapy. Barriers to information provision described included lack of resources and time, and practitioners' uncertainty regarding appropriate messages to provide. Patients wanted more information regarding diet, exercise and weight during treatment time. The findings of this study suggest an increase in provision of diet, exercise and weight management information is needed. This information should be evidence-based and delivered at an appropriate time by the preferred health care professional. It would also be beneficial to implement protocols regarding assessment of weight during treatment.

Economic evaluation for protein and energy supplementation in adults: opportunities to strengthen the evidence.

Malnutrition is a costly problem for health care systems internationally. Malnourished individuals require longer hospital stays and more intensive nursing care than adequately nourished individuals and have been estimated to cost an additional £7.3 billion in health care expenditures in the United Kingdom alone. However, treatments for malnutrition have rarely been considered from an economic perspective. The aim of this systematic review was to identify the cost effectiveness of using protein and energy supplementation as a widely used intervention to treat adults with and at risk of malnutrition. Papers were identified that included economic evaluations of protein or energy supplementation for the treatment or prevention of malnutrition in adults. While the variety of outcome measures reported for cost-effectiveness studies made synthesis of results challenging, cost-benefit studies indicated that the savings for the health system could be substantial due to reduced lengths of hospital stay and less intensive use of health services after discharge. In summary, the available economic evidence indicates that protein and energy supplementation in treatment or prevention of malnutrition provides an opportunity to improve patient wellbeing and lower health system costs.

Hepatitis B virus wild-type and rtN236T populations show similar early HBV DNA decline in adefovir refractory patients on a tenofovir-based regimen.

Hepatitis B virus (HBV) pol/RT mutations that confer clinical resistance to tenofovir disoproxil fumarate (TDF) have not been detected to date. In vitro, the rtN236T adefovir dipivoxil (ADV)-associated resistance mutation confers low-level cross-resistance to tenofovir: 3- to 13-fold changes in EC(50) from wild type. This study evaluated the clinical response of rtN236T mutant viruses by comparing their early viral load decay kinetics to wild-type viruses in chronic HBV monoinfected patients harbouring rtN236T prior to initiating TDF or emtricitabine (FTC)/TDF therapy. Baseline samples (n = 105) from adefovir refractory patients were tested for the presence of rtN236T using a highly sensitive allele-specific PCR assay with an rtN236T detection cut-off of 0.5%. The rtN236T mutation was detected at baseline in 14.3% (14/98) of analysable patient samples (0.5-93.2%, rtN236T percentage range). The median change in total HBV DNA at week 24 was comparable for patients with rtN236T detected at baseline (-3.7 log(10) copies/mL, n = 14) as compared to patients with wild-type HBV (-3.2 log(10) copies/mL, n = 90). In patients with rtN236T, wild-type and rtN236T mutant virus showed similar rates of HBV DNA decline with no statistically significant difference observed at week 4. Moreover, the proportion of rtN236T remained unchanged in patients in either arm of the study during treatment. In conclusion, the rtN236T mutant virus showed similar HBV DNA decline kinetics to wild-type virus in adefovir refractory patients who switched to TDF or FTC/TDF. Despite low levels of cross-resistance in vitro, TDF similarly suppresses wild-type and rtN236T mutant viruses in vivo.

A comparison of flow-mediated dilatation and peripheral artery tonometry for measurement of endothelial function in healthy individuals and patients with peripheral arterial disease.

OBJECTIVE: Flow-mediated dilatation (FMD) and peripheral artery tonometry (PAT) are commonly used methods for assessing endothelial function in a research setting but it is unclear how well they correlate. This study aimed to compare and correlate these methods in patients with peripheral arterial disease (PAD) and in healthy individuals. MATERIALS AND METHODS: FMD and PAT measurements were obtained as samples of convenience from 26 patients with PAD and 25 healthy subjects. FMD was defined as the percentage increase in the brachial artery diameter after distal occlusion and PAT was measured using the reactive hyperaemia index (RHI). RESULTS: Patients with PAD had a significantly lower FMD than healthy subjects (2.43% vs. 5.80%, p < 0.001). No difference was found in RHI between the two groups. No correlation was found between the FMD and RHI in subjects with PAD (r = 0.284, p = 0.160), in healthy subjects (r = 0.153, p = 0.464) or when both groups were combined (r = 0.174, p = 0.22). CONCLUSION: The lack of change in RHI in PAD patients suggests that PAT is not a sensitive measure of endothelial function. The lack of correlation suggests that FMD and PAT are not interchangeable. PAT should not be used as a substitute for FMD as a measure of endothelial function.