Microbiome changes associated with acute and chronic pancreatitis: A systematic review.

BACKGROUND: Altered intestinal microbiota has been reported in pancreatic disorders, however, it remains unclear whether these changes alter the course of disease in patients with acute (AP) and chronic pancreatitis (CP), or whether these disease states alter the environment to enable pathogenic microbial composition changes to occur. We undertook a systematic review to characterize the gut microbiome in pancreatitis patients. METHODS: MEDLINE and EMBASE were searched for studies on microbiota in pancreatitis published from January 1, 2000 to June 5, 2020. Animal studies, reviews, case reports, and non-English articles were excluded. A frequency analysis was performed for outcomes reported in ≥2 studies and studies were analyzed for risk of bias and quality of evidence. RESULTS: 22 papers met inclusion criteria; 15 included AP, 7 included CP. No studies were appropriately designed to assess whether alterations in the gut microbiome exacerbate pancreatitis or develop as a result of pancreatitis. We did identify several patterns of microbiome changes that are associated with pancreatitis. The gut microbiome demonstrated decreased alpha diversity in 3/3 A P studies and 3/3 C P studies. Beta diversity analysis revealed differences in bacterial community composition in the gut microbiome in 2/2 A P studies and 3/3 C P studies. Functionally, gut microbiome changes were associated with infectious pathways in AP and CP. Several studies suffered from high risk of bias and inadequate quality. CONCLUSIONS: Detecting differences in microbial composition associated with AP and CP may represent a diagnostic tool. Appropriately controlled longitudinal studies are needed to determine whether microbiome changes are causative or reactive in pancreatitis.

Immune status and the efficacy of adjuvant radiotherapy for patients with localized Merkel cell carcinoma of the head and neck.

PURPOSE: Immunosuppressed (IS) patients are at increased risk for developing Merkel cell carcinoma (MCC) with worsened outcomes compared to immunocompetent (IC) patients. We sought to determine the effects of immune status on the efficacy of adjuvant RT regarding OS for patients with stage I, II or III (localized) MCC of the head and neck. METHODS/PATIENTS: The National Cancer Database was queried for patients with resected, localized MCC of the head and neck with known immune status. Kaplan-Meier methods were used to describe OS. Log-rank tests, multivariable Cox regression models and interaction effect testing were used to compare OS by subgroup categorized by patient and treatment factors including immune status and adjuvant RT receipt. RESULTS: A total of 892 (89.6%) IC and 104 (10.4%) IS patients with MCC of the head and neck were included. Adjuvant RT was associated with improved 3-year OS rate for both IS patients (49.4% vs. 35.5%, p = 0.0467) and stage I/II IC patients (72.4% vs. 62.9%, p = 0.0092). Adjuvant RT was associated with decreased hazard of death (HR 0.77, 95% CI 0.62-0.95). Interaction effect testing did not demonstrate a difference in the efficacy of adjuvant RT on OS between IC and IS status (p = 0.157). CONCLUSIONS: In this NCDB analysis, adjuvant RT was associated with decreased hazard of death for patients with localized MCC of the head and neck regardless of immune status and should be considered for both IS and IC patients.

Repeat gamma knife stereotactic radiosurgery in the treatment of trigeminal neuralgia: A single-center experience and focused review of the literature.

OBJECTIVES: Repeat Gamma Knife stereotactic radiosurgery (GKSR) for refractory trigeminal neuralgia (TGN) is an increasingly common practice. Prior studies have reported varying success rates and incidence of trigeminal nerve dysfunction following repeated GKSR. We report treatment outcomes and toxicity in patients following repeat GKSR for TGN at the University of Alabama at Birmingham (UAB) with a focused review of the literature. METHODS: We retrospectively reviewed medical records of 55 TGN patients re-treated with radiosurgery using the Leksell Gamma Knife® at the University of Alabama at Birmingham between 1996 and 2012. Outcomes were defined using the Modified Marseille Scale. Demographics, prior treatments and symptom duration were correlated with outcomes. RESULTS: Eighteen patients (33%) achieved Marseille Class I or II, 14 (25%) Class III or IV, and 23 (42%) Class V at a mean follow-up of 14.4 months. Twenty-five patients (45%) developed new trigeminal nerve dysfunction after re-treatment. Of these, four (16%) did not develop dysfunction until subsequent microvascular decompression (MVD) for inadequate symptom relief. CONCLUSIONS: Although more than half of the patients undergoing repeat GKSR for refractory TGN maintained excellent or good outcomes (Marseille classes I-IV) at an average follow-up of 14.4 months, neither age, gender, nor pre-treatment duration of symptoms or interval between treatments had a statistically significant effect on outcomes. Following repeat GKSR, patients have increased risk for new-onset trigeminal nerve dysfunction and those undergoing MVD after repeat GKSR may have an increased risk for new-onset trigeminal nerve dysfunction.

Estimating 3-dimensional surface areas of small scleractinian corals.

Stressor-response research on stony corals in the laboratory relies on detecting relatively small changes in the size of coral fragments throughout the course of an experiment. Coral colonies are complex, three-dimensional (3D) communities of organisms, so small changes in size are best detected by changes in 3D surface area. Traditional methods to estimate 3D coral surface area commonly require destruction of the sample, thereby eliminating repeat measurements and the ability to calculate growth rate. However, non-destructive two-dimensional (2D) photogrammetry can be used if defensible relationships with 3D surface area can be established. In this study, 165 coral skeletons representing four stony coral species (Pocillopora damicornis, Madracis mirabilis, Orbicella faveolata, Porites porites) were photographed in 2D (top and side views) and then imaged with 3D laser scanning. Significant linear relationships were found between the 3D surface areas (laser) and the sum of various combinations of top and side view surface areas captured by 2D digital photography. The relationships were very strong for simple colony shapes and more variable as coral fragments increased in size and complexity. This study demonstrates an efficient method for obtaining estimates of 3D coral surface area from non-destructive 2D photogrammetry, allowing measurement of growth rate throughout experimental exposure periods.

Assessing land use, sedimentation, and water quality stressors as predictors of coral reef condition in St. Thomas, U.S. Virgin Islands.

Coral reef condition on the south shore of St. Thomas, U.S. Virgin Islands, was assessed at various distances from Charlotte Amalie, the most densely populated city on the island. Human influence in the area includes industrial activity, wastewater discharge, cruise ship docks, and impervious surfaces throughout the watershed. Anthropogenic activity was characterized using a landscape development intensity (LDI) index, sedimentation threat (ST) estimates, and water quality (WQ) impairments in the near-coastal zone. Total three-dimensional coral cover, reef rugosity, and coral diversity had significant negative coefficients for LDI index, as did densities of dominant species Orbicella annularis, Orbicella franksi, Montastraea cavernosa, Orbicella faveolata, and Porites porites. However, overall stony coral colony density was not significantly correlated with stressors. Positive relationships between reef rugosity and ST, between coral diversity and ST, and between coral diversity and WQ were unexpected because these stressors are generally thought to negatively influence coral growth and health. Sponge density was greater with higher disturbance indicators (ST and WQ), consistent with reports of greater resistance by sponges to degraded water quality compared to stony corals. The highest FoRAM (Foraminifera in Reef Assessment and Monitoring) indices indicating good water quality were found offshore from the main island and outside the harbor. Negative associations between stony coral metrics and LDI index have been reported elsewhere in the Caribbean and highlight LDI index potential as a spatial tool to characterize land-based anthropogenic stressor gradients relevant to coral reefs. Fewer relationships were found with an integrated stressor index but with similar trends in response direction.

Early cathepsin K degradation of type II collagen in vitro and in vivo in articular cartilage.

OBJECTIVE: To characterize the initial events in the cleavage of type II collagen mediated by cathepsin K and demonstrate the presence of the resulting products in human and equine articular osteoarthritic cartilage. DESIGN: Equine type II collagen was digested with cathepsin K and the cleavage products characterized by mass spectrometry. Anti-neoepitope antibodies were raised against the most N-terminal cleavage products and used to investigate the progress of collagen cleavage, in vitro, and the presence of cathepsin K-derived products in equine and human osteoarthritic cartilage. RESULTS: Six cathepsin K cleavage sites distributed throughout the triple helical region were identified in equine type II collagen. Most of the cleavages occurred following a hydroxyproline residue. The most N-terminal site was within three residues of the previously identified site in bovine type II collagen. Western blotting using anti-neoepitope antibodies showed that the initial cleavages occurred at the N-terminal sites and this was followed by more extensive degradation resulting in products too small to be resolved by SDS gel electrophoresis. Immunohistochemical staining of cartilage sections from equine or human osteoarthritic joints showed staining in lesional areas which was not observed in non-arthritic sites. CONCLUSIONS: Cathepsin K cleaves triple helical collagen by erosion from the N-terminus and with subsequent progressive cleavages. The liberated fragments can be detected in osteoarthritic cartilage and may represent useful biomarkers for disease activity.

Dietary Iodine Sufficiency and Moderate Insufficiency in the Lactating Mother and Nursing Infant: A Computational Perspective.

The Institute of Medicine recommends that lactating women ingest 290 µg iodide/d and a nursing infant, less than two years of age, 110 µg/d. The World Health Organization, United Nations Children's Fund, and International Council for the Control of Iodine Deficiency Disorders recommend population maternal and infant urinary iodide concentrations ≥ 100 µg/L to ensure iodide sufficiency. For breast milk, researchers have proposed an iodide concentration range of 150-180 µg/L indicates iodide sufficiency for the mother and infant, however no national or international guidelines exist for breast milk iodine concentration. For the first time, a lactating woman and nursing infant biologically based model, from delivery to 90 days postpartum, was constructed to predict maternal and infant urinary iodide concentration, breast milk iodide concentration, the amount of iodide transferred in breast milk to the nursing infant each day and maternal and infant serum thyroid hormone kinetics. The maternal and infant models each consisted of three sub-models, iodide, thyroxine (T4), and triiodothyronine (T3). Using our model to simulate a maternal intake of 290 µg iodide/d, the average daily amount of iodide ingested by the nursing infant, after 4 days of life, gradually increased from 50 to 101 µg/day over 90 days postpartum. The predicted average lactating mother and infant urinary iodide concentrations were both in excess of 100 µg/L and the predicted average breast milk iodide concentration, 157 µg/L. The predicted serum thyroid hormones (T4, free T4 (fT4), and T3) in both the nursing infant and lactating mother were indicative of euthyroidism. The model was calibrated using serum thyroid hormone concentrations for lactating women from the United States and was successful in predicting serum T4 and fT4 levels (within a factor of two) for lactating women in other countries. T3 levels were adequately predicted. Infant serum thyroid hormone levels were adequately predicted for most data. For moderate iodide deficient conditions, where dietary iodide intake may range from 50 to 150 µg/d for the lactating mother, the model satisfactorily described the iodide measurements, although with some variation, in urine and breast milk. Predictions of serum thyroid hormones in moderately iodide deficient lactating women (50 µg/d) and nursing infants did not closely agree with mean reported serum thyroid hormone levels, however, predictions were usually within a factor of two. Excellent agreement between prediction and observation was obtained for a recent moderate iodide deficiency study in lactating women. Measurements included iodide levels in urine of infant and mother, iodide in breast milk, and serum thyroid hormone levels in infant and mother. A maternal iodide intake of 50 µg/d resulted in a predicted 29-32% reduction in serum T4 and fT4 in nursing infants, however the reduced serum levels of T4 and fT4 were within most of the published reference intervals for infant. This biologically based model is an important first step at integrating the rapid changes that occur in the thyroid system of the nursing newborn in order to predict adverse outcomes from exposure to thyroid acting chemicals, drugs, radioactive materials or iodine deficiency.

Vaccine acceptance, hesitancy and refusal in Canada: Challenges and potential approaches.

"Vaccine hesitancy" is a concept used frequently in vaccination discourse and is challenging previously held perspective that individual vaccination attitudes and behaviours are a simple dichotomy of accept or reject. Given the importance of achieving high vaccine coverage in Canada to avoid vaccine preventable diseases and their consequences, vaccine hesitancy is an important issue that needs to be addressed. This article describes the scope and causes of vaccine hesitancy in Canada and proposes potential approaches to address it.

Contrasting responses of coral reef fauna and foraminiferal assemblages to human influence in La Parguera, Puerto Rico.

Coral reef biota including stony corals, sponges, gorgonians, fish, benthic macroinvertebrates and foraminifera were surveyed in coastal waters near La Parguera, in southwestern Puerto Rico. The goal was to evaluate sensitivity of coral reef biological indicators to human disturbance. Proxies for human disturbance were measured as distance to town (DTT) and rankings of a low-level sediment contamination gradient analyzed from a previous study. Contaminant rank and DTT showed that percent mud, stony coral taxa richness, reef rugosity, and numbers of invertebrates and sponges were higher at sites closer to human disturbance, but a foraminiferal assemblage index was significantly lower at sites with higher proxies for human disturbance. Fish indicators showed no significant relationships with human activity, but associations between fish community measures and certain measures of stony corals, gorgonians and sponges were found. Contrasting responses between foraminifera and reef organisms may be due to greater exposure and sensitivity of foraminifera to sediment contaminants.

Dynamic symmetry-breaking in a simple quantum model of magneto-electric rectification, optical magnetization, and harmonic generation.

The state mixings necessary to mediate three new optical nonlinearities are shown to arise simultaneously and automatically in a 2-level atom with an ℓ = 0 ground state and an ℓ = 1 excited state that undergoes a sequence of electric and magnetic dipole-allowed transitions. The treatment is based on an extension of dressed state theory that includes quantized electric and magnetic field interactions. Magneto-electric rectification, transverse magnetization, and second-harmonic generation are shown to constitute a family of nonlinear effects that can take place regardless of whether inversion is a symmetry of the initial unperturbed system or not. Interactions driven jointly by the optical electric and magnetic fields produce dynamic symmetry-breaking that accounts for the frequency, the intensity dependence, and the polarization of induced magnetization in prior experiments. This strong field quantum model explains not only how a driven 2-level system may develop nonlinear dipole moments that are forbidden between or within its stationary states, but it also broadens the class of materials suitable for optical energy conversion applications and magnetic field generation with light so as to include all transparent dielectrics.

Extended venous thromboembolism prophylaxis in patients undergoing hip fracture surgery - the SAVE-HIP3 study.

There is currently limited information available on the benefits and risks of extended thromboprophylaxis after hip fracture surgery. SAVE-HIP3 was a randomised, double-blind study conducted to evaluate the efficacy and safety of extended thromboprophylaxis with the ultra-low molecular-weight heparin semuloparin compared with placebo in patients undergoing hip fracture surgery. After a seven- to ten-day open-label run-in phase with semuloparin (20 mg once daily subcutaneously, initiated post-operatively), patients were randomised to once-daily semuloparin (20 mg subcutaneously) or placebo for 19 to 23 additional days. The primary efficacy endpoint was a composite of any venous thromboembolism (VTE; any deep-vein thrombosis and non-fatal pulmonary embolism) or all-cause death until day 24 of the double-blind period. Safety parameters included major and clinically relevant non-major bleeding, laboratory data, and treatment-emergent adverse events (TEAEs). Extended thromboprophylaxis with semuloparin demonstrated a relative risk reduction of 79% in the rate of any VTE or all-cause death compared with placebo (3.9% vs 18.6%, respectively; odds ratio 0.18 (95% confidence interval 0.07 to 0.45), p < 0.001). Two patients in the semuloparin group and none in the placebo group experienced clinically relevant bleeding. TEAE rates were similar in both groups. In conclusion, the SAVE-HIP3 study results demonstrate that patients undergoing hip fracture surgery benefit from extended thromboprophylaxis.

Gene profile identifies zinc transporters differentially expressed in normal human organs and human pancreatic cancer.

Deregulated expression of zinc transporters was linked to several cancers. However, the detailed expression profile of all human zinc transporters in normal human organs and in human cancer, especially in pancreatic cancer is not available. The objectives of this study are to investigate the complete expression patterns of 14 ZIP and 10 ZnT transporters in a large number of normal human organs and in human pancreatic cancer tissues and cell lines. We examined the expression patterns of ZIP and ZnT transporters in 22 different human organs and tissues, 11 pairs of clinical human pancreatic cancer specimens and surrounding normal/benign tissues, as well as 10 established human pancreatic cancer cell lines plus normal human pancreatic ductal epithelium (HPDE) cells, using real time RT-PCR and immunohistochemistry. The results indicate that human zinc transporters have tissue specific expression patterns, and may play different roles in different organs or tissues. Almost all the ZIPs except for ZIP4, and most ZnTs were down-regulated in human pancreatic cancer tissues compared to the surrounding benign tissues. The expression patterns of individual ZIPs and ZnTs are similar among different pancreatic cancer lines. Those results and our previous studies suggest that ZIP4 is the only zinc transporter that is significantly up-regulated in human pancreatic cancer and might be the major zinc transporter that plays an important role in pancreatic cancer growth. ZIP4 might serve as a novel molecular target for pancreatic cancer diagnosis and therapy.

Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE.

BACKGROUND: Semuloparin is a novel ultra-low-molecular-weight heparin under development for venous thromboembolism (VTE) prevention in patients at increased risk, such as surgical and cancer patients. OBJECTIVES: Three Phase III studies compared semuloparin and enoxaparin after major orthopedic surgery: elective knee replacement (SAVE-KNEE), elective hip replacement (SAVE-HIP1) and hip fracture surgery (SAVE-HIP2). PATIENTS/METHODS: All studies were multinational, randomized and double-blind. Semuloparin and enoxaparin were administered for 7-10 days after surgery. Mandatory bilateral venography was to be performed between days 7 and 11. The primary efficacy endpoint was a composite of any deep vein thrombosis, non-fatal pulmonary embolism or all-cause death. Safety outcomes included major bleeding, clinically relevant non-major (CRNM) bleeding, and any clinically relevant bleeding (major bleeding plus CRNM). RESULTS: In total, 1150, 2326 and 1003 patients were randomized in SAVE-KNEE, SAVE-HIP1 and SAVE-HIP2, respectively. In all studies, the incidences of the primary efficacy endpoint were numerically lower in the semuloparin group vs. the enoxaparin group, but the difference was statistically significant only in SAVE-HIP1. In SAVE-HIP1, clinically relevant bleeding and major bleeding were significantly lower in the semuloparin vs. the enoxaparin group. In SAVE-KNEE and SAVE-HIP2, clinically relevant bleeding tended to be higher in the semuloparin group, but rates of major bleeding were similar in the two groups. Other safety parameters were generally similar between treatment groups. CONCLUSIONS: Semuloparin was superior to enoxaparin for VTE prevention after hip replacement surgery, but failed to demonstrate superiority after knee replacement surgery and hip fracture surgery. Semuloparin and enoxaparin exhibited generally similar safety profiles.

Genomic sequencing of key genes in mouse pancreatic cancer cells.

Pancreatic cancer is a multiple genetic disorder with many mutations identified during the progression. Two mouse pancreatic cancer cell lines were established which showed different phenotype in vivo: a non-metastatic cell line, Panc02, and a highly metastatic cell line, Panc02-H7, a derivative of Panc02. In order to investigate whether the genetic mutations of key genes in pancreatic cancer such as KRAS, TP53 (p53), CDKN2A (p16), SMAD4, ZIP4, and PDX-1 contribute to the phenotypic difference of these two mouse pancreatic cancer cells, we sequenced the exonic regions of these key genes in both cell lines and in the normal syngeneic mouse pancreas and compared them with the reference mouse genome sequence. The exons of KRAS, SMAD4, CDKN2A (p16), TP53 (p53), ZIP4, and PDX-1 genes were amplified and the genotype of these genes was determined by Sanger sequencing. The sequences were analyzed with Sequencher software. A mutation in SMAD4 was identified in both cell lines. This homozygote G to T mutation in the first position of codon 174 (GAA) generated a stop codon resulting in the translation of a truncated protein. Further functional analysis indicates that different TGF-ß/SMAD signaling pathways were involved in those two mouse cell lines, which may explain the phonotypic difference between the two cells. A single nucleotide polymorphism (SNP) in KRAS gene (TAT to TAC at codon 32) was also identified in the normal pancreas DNA of the syngenic mouse and in both derived tumoral Panc02 and Panc02-H7 cells. No mutation or SNP was found in CDKN2A (p16), TP53 (p53), ZIP4, and PDX-1 genes in these two cell lines. The absence of mutations in genes such as KRAS, TP53, and CDKN2A, which are considered as key genes in the development of human pancreatic cancer suggests that SMAD4 might play a central and decisive role in mouse pancreatic cancer. These results also suggest that other mechanisms are involved in the substantial phenotypic difference between these two mouse pancreatic cancer cell lines. Further studies are warranted to elucidate the molecular pathways that lead to the aggressive metastatic potential of Panc02-H7.

Updated survival and outcomes for older adults with inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel: analysis of a phase III trial from the Hoosier Oncology Group (HOG) and US Oncology.

BACKGROUND: Concurrent chemoradiation with etoposide and cisplatin (EP/XRT) is standard treatment for inoperable stage III locally advanced non-small-cell lung cancer (LA-NSCLC). Consolidation docetaxel (D; Taxotere) after EP/XRT resulted in increased toxicity but no improvement in survival compared with observation (O). We report updated survival for the entire study population and include an analysis of efficacy and tolerability of EP/XRT with or without D in patients aged ≥ 70 years. PATIENTS AND METHODS: Hoosier Oncology Group LUN 01-24 enrolled 243 patients with LA-NSCLC and randomized 166 after EP/XRT to three cycles of D versus O. the trial was terminated after an analysis of the first 203 patients demonstrated futility of D. RESULTS: Median survival time (MST) for the overall study population was 21.5 months, and 3-, 4-, and 5-year survival rates were 30.7%, 18.0%, and 13.9%, respectively. No differences in MST or 3-year survival were noted between D and O arms. Older patients had similar MST (17.1 versus 22.8 months for younger patients, P = 0.15) but higher rates of grade 3/4 toxicity and hospitalization during induction. CONCLUSIONS: Consolidation docetaxel after EP/XRT does not improve survival in LA-NSCLC. Fit older adults with LA-NSCLC benefit from concurrent chemoradiation similarly as younger patients but experience higher rates of hospitalization and toxicity.

Effects of forage NDF content and body condition score on forage intake by Holstein-Friesian dairy cows in the dry period.

This study used individual weekly results for 160 non-lactating Holstein-Friesian dairy cows in the last 5 weeks of gestation to develop regression equations based on forage NDF content and individual body condition score (BCS) for predicting dry matter (DM) intake. Results were used from treatments in which cows received the same forage and no concentrates throughout the dry period. Ten different conserved forages, either grass silages or mixtures of grass silage and barley straw, were fed in six different experiments and forage NDF ranged from 452 to 689 g/kg DM. On average cows gained 390 g live weight per day, which is less than conceptus growth at this stage - suggesting some mobilisation of maternal tissues to support conceptus growth. BCS remained unchanged at 2.5 over the dry period. DM intake declined from 10.79 kg/day 5 weeks before calving to 9.32 kg/day in the week before calving, with half of this decline occurring in the final week before calving. Intake as a percentage of live weight was moderately predicted (R2 = 0.61 for the entire period) from measures of diet composition (NDF) and cow state (BCS). There were highly significant negative effects of forage NDF and increased BCS on DM intake. The effect of BCS on DM intake was greatly reduced in the week before calving, possibly as a result of a change in metabolic priorities from gaining to losing body reserves.

Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients.

The definition of major bleeding varies between studies on surgical patients, particularly regarding the criteria for surgical wound-related bleeding. This diversity contributes to the difficulties in comparing data between trials. The Scientific and Standardization Committee (SSC), through its subcommittee on Control of Anticoagulation, of the International Society on Thrombosis and Haemostasis has previously published a recommendation for a harmonized definition of major bleeding in non-surgical studies. That definition has been adopted by the European Medicines Agency and is currently used in several non-surgical trials. A preliminary proposal for a parallel definition for surgical studies was presented at the 54(th) Annual Meeting of the SSC in Vienna, July 2008. Based on those discussions and further consultations with European and North American surgeons with experience from clinical trials a definition has been developed that should be applicable to all agents that interfere with hemostasis. The definition and the text that follows have been reviewed and approved by relevant co-chairs of the subcommittee and by the Executive Committee of the SSC. The intention is to seek approval of this definition from the regulatory authorities to enhance its incorporation into future clinical trial protocols.

Effects of silage digestibility on intake and body reserves of dry cows and performance in the first part of the next lactation.

This experiment evaluated different strategies for allocating first-cut grass silages to dry dairy cows that had low body-condition score (BCS) at drying off. A total of 48 moderately yielding Holstein-Friesian cows were used, receiving one of three dietary treatments in the dry period and a single lactation diet based on a flat-rate of concentrates and grass silage ad libitum. Throughout the dry period, one group received a low-digestibility silage (harvested 15 June 1998; LL; metabolisable energy (ME) = 10.3 MJ/kg dry matter (DM)) and a second group received a high-digestibility silage (harvested 9 May 1998, HH; ME = 11.7 MJ/kg DM). A third strategy (LH) offered the low-digestibility silage in the early dry period and the high-digestibility silage in the final 3 weeks before calving. The silages had very different crude protein concentrations (144 and 201 g/kg DM) and intakes were widely divergent (10.1 v. 13.5 kg DM/day) across the dry period. No concentrates were fed during the dry period. Silage quality had a very large effect on liveweight change, with treatment means of 0.32 and 1.75 kg/day for LL and HH, respectively. BCS changes followed a similar pattern, though no cows became over-conditioned and blood metabolites were within normal ranges. Increased silage digestibility in the late dry period led to a substantial increase in milk fat concentration and a smaller increase in milk protein concentration, the latter confined to the first full week of lactation. Depression of milk fat appears related to low blood glucose when dry cows in low body condition are fed at a low level. The LH strategy avoided the tendency for lower milk yields and fat concentration that resulted from feeding the low-digestibility silage until calving. This strategy also avoided the higher calf weights that resulted from feeding the high-digestibility silage in the early dry period.