Comparison of greenhouse gas emissions from sheep measured using both respiration and portable accumulation chambers.

Methane (CH4) is a potent gas produced by ruminants, and new measurement techniques are required to generate large datasets suitable for genetic analysis. One such technique are portable accumulation chambers (PAC), a short-term sampling method. The objectives of the current study were to explore the relationship between CH4 and carbon dioxide (CO2) output measured using both PAC and respiration chambers (RC) in growing lambs, and separately investigate the relationship among CH4, CO2 and measured ad libitum DM intake (DMI). Methane, CO2 and DMI were measured on 30 Suffolk and 30 Texel ewe lambs (age 253 ± 12 days) using the RC and PAC sequentially. The experiment was conducted over a 14-day period, with DMI measured from days 1 to 14; measurements in RC were conducted from days 10 to 12, while measurements in PAC were taken twice, the day immediately prior to the lambs entering the RC (day 9; PAC Pre-RC) and on the day lambs exited the RC (day 13; PAC Post-RC). Greater CH4 and CO2 output was measured in the RC than in the PAC (P < 0.01); similarly mean CH4 yield was greater when measured in the RC (15.39 ± 0.452 g CH4/kg DMI) compared to PAC (8.01 ± 0.767 g CH4/kg DMI). A moderate correlation of 0.37 was found between CH4 output measured in PAC Pre-RC and the RC, the corresponding regression coefficient of CH4 output measured in the RC regressed on CH4 output measured in PAC Pre-RC was close to unity (0.74; SE 0.224). The variance of CH4 and CO2 output within the measurement technique did not differ from each other (P > 0.05). Moderate to strong correlations were found between CH4 and CO2 per kg of live weight and CH4 and CO2 yield. Results from this study highlight the suitability of PAC as a ranking tool to rank animals based on their gaseous output when compared to the RC. However, repeated measurements separated by several days may be beneficial if precise rankings are required. Given the close to unity regression coefficient of CH4 output measured in the RC regressed on CH4 output measured in PAC Pre-RC suggests that PAC could also be potentially used to estimate absolute CH4 output; however, further research is required to substantiate this claim. When DMI is unknown, CH4 and CO2 per kg of live weight are a suitable alternative to the measurement of CH4 and CO2 yield.

Milk as diagnostic fluid for udder health management.

BACKGROUND: Mastitis is the major disease affecting milk production of dairy cattle, and milk is an obvious substrate for the detection of both the inflammation and its causative infectious agents at quarter, cow, or herd levels. In this review, we examine the use of milk to detect inflammation based on somatic cell count (SCC) and other biomarkers, and for the detection of mastitis pathogens through culture-based and culture-free methods. FINDINGS: The use of SCC at a cow or bulk milk level to guide udder health management in lactation is well-established, and SCC is increasingly used to guide selective dry cow treatment. Other markers of inflammation include electrical conductivity, which is used commercially, and markers of disease severity such as acute phase proteins but are not pathogen-specific. Some pathogen-specific markers based on humoral immune responses are available, but their value in udder health management is largely untested. Commercial pathogen detection is based on culture or polymerase chain reaction, with other tests, for example, loop-mediated isothermal amplification or 16S microbiome analysis still at the research or development stage. Matrix-assisted laser desorption ionisation time of flight (MALDI-ToF) is increasingly used for the identification of cultured organisms whilst application directly to milk needs further development. Details of test sensitivity, specificity, and use of the various technologies may differ between quarter, cow, and bulk milk applications. CONCLUSIONS: There is a growing array of diagnostic assays that can be used to detect markers of inflammation or infection in milk. The value of some of these methods in on-farm udder health improvement programs is yet to be demonstrated whilst methods with proven value may be underutilised.

Low prevalence of antimicrobial resistant organisms (methicillin resistant Staphylococcus aureus, extended beta-lactamase producing Enterobacteriaceae, and vancomycin resistant enterococci) in bulk tank milk in New South Wales, Australia.

OBJECTIVE: Estimate the presence of methicillin resistant Staphylococcus aureus (MRSA), extended beta-lactamase (ESBL) producing Enterobacteriaceae, and vancomycin resistant enterococci (VRE) in bulk tank milk in dairy herds in New South Wales (NSW), Australia. METHODS: Bulk tank milk samples (n = 80) were collected from dairy farms (n = 40, i.e. 2 per farm) in NSW during 2021. Bacteria were cultured using selective chromogenic indicator media with isolate identity confirmed using biochemical testing, Gram stain, and MALDI-TOF mass spectroscopy. Antimicrobial resistance (AMR) was confirmed using antibiotic disk diffusion. RESULTS: No samples tested positive to the targeted AMR organisms. CONCLUSION: The prevalence of MRSA, ESBL-producing Enterobacteriaceae, and VRE is low in NSW dairy herds.

Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study.

BACKGROUND: MRT5005, a codon-optimized CFTR mRNA, delivered by aerosol in lipid nanoparticles, was designed as a genotype-agnostic treatment for CF lung disease. METHODS: This was a randomized, double-blind, placebo-controlled Phase 1/2 study performed in the US. Adults with 2 severe class I and/or II CFTR mutations and baseline ppFEV1 values between 50 and 90% were randomized 3:1 (MRT5005: placebo). Six dose levels of MRT5005 (4, 8, 12, 16, 20, and 24 mg) or placebo (0.9% Sodium Chloride) were administered by nebulization. The single ascending dose cohort was treated over a range from 8 to 24 mg; the multiple ascending dose cohort received five weekly doses (range 8-20 mg); and the daily dosing cohort received five daily doses (4 mg). RESULTS: A total of 42 subjects were assigned to MRT5005 [31] or placebo [11]. A total of 14 febrile reactions were observed in 10 MRT5005-treated participants, which were mild [3] or moderate [11] in severity; two subjects discontinued related to these events. Additionally, two MRT5005-treated patients experienced hypersensitivity reactions, which were managed conservatively. The most common treatment emergent adverse events were cough and headache. No consistent effects on FEV1 were noted. CONCLUSIONS: MRT5005 was generally safe and well tolerated through 28 days of follow-up after the last dose, though febrile and hypersensitivity reactions were noted. The majority of these reactions resolved within 1-2 days with supportive care allowing continued treatment with MRT5005 and careful monitoring. In this small first-in-human study, FEV1 remained stable after treatment, but no beneficial effects on FEV1 were observed.

A framework for evaluation of on-farm mastitis diagnostics in Australia.

Numerous culture-based diagnostics are available on the Australian and international markets for on-farm detection of bacterial pathogens in milk. Use of such diagnostics may provide an opportunity to improve the prudent use of antimicrobials in udder health management. Farms are low-resource settings in terms of diagnostic microbiology capacity. The World Health Organisation has identified criteria for the evaluation of diagnostic tests in low resource settings based on Accuracy, Sensitivity, Specificity, User-friendliness, being Rapid or Robust, Equipment-free and being Deliverable (ASSURED). Here, we review how those criteria can be interpreted in the context of microbiological diagnosis of mastitis pathogens, and how on-farm diagnostics that are currently available in Australia perform relative to ASSURED criteria. This evaluation identifies multiple trade-offs, both with regard to scientific criteria and with regards to convenience criteria. More importantly, the purpose of testing may differ between farms, and test performance should be evaluated relative to its intended use. The ability of on-farm mastitis diagnostics to inform mastitis treatment decision-making in a timely and cost-effective manner depends not just on test characteristics but also on farm-specific pathogen prevalence, and on the farm enterprise's priorities and the farm manager's potential courses of action. With most assay evaluations to date conducted in professional laboratories, there is a surprising dearth of information on how well any of the diagnostic tests perform on-farm and, indeed, of the on-farm decision-making processes that they aim to inform.

Characterizing CFTR modulated sweat chloride response across the cf population: Initial results from the CHEC-SC study.

BACKGROUND: CHEC-SC is an ongoing epidemiologic study characterizing modulator-induced sweat chloride (SC) responses across the CF population, with interim results available prior to the availability of triple combination modulator therapy. METHODS: Eligible participants had been prescribed a modulator for ≥90 days with re-enrollment allowed upon establishment of a new modulator. Pre-modulator SC values were obtained from chart review; post-modulator sweat was collected and analyzed locally. SC changes were descriptively summarized with biologic sex effects adjusted for age, weight, and CFTR genotype. Heterogeneity in ivacaftor SC response was characterized in relation to published CFTR functional responses. RESULTS: 1848 participants provided 2004 SC measurements, 26.2% on ivacaftor, 39.1% on lumacaftor/ivacaftor, and 34.7% on tezacaftor/ivacaftor. Average SC changes for all modulators were consistent with those reported in previous clinical studies, with greater variation in SC response observed among rarer mutations and notable shifts in the proportion with SC <60mmol/L independent of the magnitude of SC change. Ivacaftor induced in vitro CFTR functional change was significantly correlated with ivacaftor-modulated SC response (Pearson correlation= ‒0.52, 95% CI: ‒0.773, ‒0.129). Average SC change from ivacaftor to tezacaftor/ivacaftor was ‒4.9 mmol/L (n=17,95% CI:‒9.3, ‒0.5) and differed from those switching from lumacaftor/ivacaftor (10.0 mmol/L, n=139, 95% CI:7.8,12.3). Sex at birth was not associated with SC response. CONCLUSIONS: CHEC-SC is the largest study characterizing modulator-induced SC changes across the CF population. There was a strong association between ivacaftor induced in vitro CFTR function and SC response across a genotypically heterogenous cohort. Biological sex was not associated with SC response.

ECFS standards of care on CFTR-related disorders: Diagnostic criteria of CFTR dysfunction.

The spectrum of disorders involving CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction correlates with a continuous gradient of CFTR function defined by the combination of two allelic CFTR variants. CFTR-related disorders are clinical entities with features of cystic fibrosis (CF) and evidence for presence of CFTR dysfunction but not meeting criteria for diagnosis of CF. Individuals with CFTR-RDs demonstrate a wide range of CFTR activity and are still under-recognized or misclassified. The level of CFTR dysfunction may be measured in vivo (sweat testing, nasal potential difference measurements) and/or by ex vivo tests (intestinal current measurement), or indirectly indicated by CFTR variants, as alteration in sequence of the CFTR gene translates into CFTR dysfunction. CFTR bioassays can aid in the diagnosis of individuals with CF, but we lack parameters to differentiate CF from CFTR-RD. In the era of the CFTR modulators and their potential clinical benefit, it is of utmost importance to diagnose CFTR-RD as unambiguously as possible. We therefore propose the following to define compatible CFTR dysfunction in a person with a suspected diagnosis of CFTR-RD : (1) evidence of CFTR dysfunction in vivo or ex vivo in at least two different CFTR functional test types, or (2) One CFTR variant known to reduce CFTR function and evidence of CFTR dysfunction in vivo or ex vivo in at least two different CFTR functional test types, or (3) Two CFTR variants shown to reduce CFTR function, with at most one CF-causing variant.

Can we have our steak and eat it: The impact of breeding for lowered environmental impact on yield and meat quality in sheep.

Global agreements in place to reduce methane emissions in livestock are a potential threat to food security. Successful but independent breeding strategies for improved production and lower methane are in place. The unanswered questions are whether these strategies can be combined and how they impact one another, physically and economically. The New Zealand economy is largely dependent on pastoral agriculture from grazing ruminants. The sheep industry produces ∼20 million lamb carcasses for export each year primarily from grass. Methane emitted from the fermentation of forage by grazing ruminants accounts for one-third of all New Zealand's greenhouse gas emissions. Here, we use sheep selection lines bred for divergent methane production and large numbers of their relatives to determine the genetic and phenotypic correlations between enteric methane emissions, carcass yield, and meat quality. The primary objectives were to determine whether previously shown physiological differences between methane selection lines (differing by ∼12% in methane) result in a negative impact on meat production and quality by measuring close relatives. The results show no negative effects of breeding for lowered methane on meat and carcass quality. Gross methane emissions were highly correlated with liveweight and measures of carcass weight and negatively correlated with dressing-out percentage and fat yield (GR). Trends were similar but not significant for methane yield (g CH4/kg DMI). Preliminary evidence, to date, shows that breeding for low methane may result in animals with higher lean yields that are economically favorable even before carbon costs and environmental benefits are taken into account. These benefits were seen in animals measured for methane on fixed intakes and require validation on intakes that are allowed to vary.

A survey of mastitis pathogens including antimicrobial susceptibility in southeastern Australian dairy herds.

The objectives for this study were to (1) describe the pathogen profile in quarters from cows with clinical mastitis and in cows with subclinical mastitis in southeastern Australia; and (2) describe antimicrobial susceptibility among isolated pathogens. As a secondary objective, we aimed to compare antimicrobial resistance prevalence in pathogens isolated from clinical and subclinical mastitis samples. A convenience sample of dairy herds (n = 65) from 4 regions in southeastern Australia (Gippsland, Northern Victoria, Tasmania, Western Victoria) were invited to submit milk samples from cows with clinical and subclinical mastitis over a 14-mo period (January 2011 to March 2012). Farmers were instructed to collect aseptic quarter milk samples from the first 10 cases of clinical mastitis for each month of the study. In addition, farmers submitted composite milk samples from cows with subclinical mastitis at 1 or 2 sampling occasions during the study period. Aerobic culture and biochemical tests were used to identify isolates. Isolates were classified as susceptible, intermediate, or resistant to a panel of antimicrobial agents based on the zone of growth inhibition around antimicrobial-impregnated disks, with antimicrobial resistance (AMR) classified as nonsusceptibility by combining intermediate and resistant groups into a single category. Generalized linear mixed models were used to compare the prevalence of AMR between clinical and subclinical mastitis isolates. For clinical mastitis samples (n = 3,044), 472 samples (15.5%) were excluded for contamination. Of the remaining samples (n = 2,572), the most common results were Streptococcus uberis (39.2%), no growth (27.5%), Staphylococcus aureus (10.6%), Escherichia coli (8.4%), and Streptococcus dysgalactiae (6.4%). For subclinical mastitis samples (n = 1,072), 425 (39.6%) were excluded due to contamination. Of the remaining samples (n = 647), the most common results were no growth (29.1%), Staph. aureus (29.1%), and Strep. uberis (21.6%). The prevalence of AMR among common isolates was low for the majority of antimicrobial agents. Exploratory analysis found that the probability of Staph. aureus demonstrating resistance to penicillin was 5.16 times higher (95% confidence interval: 1.68, 15.88) in subclinical isolates relative to clinical Staph. aureus isolates. A similar association was observed for amoxicillin with subclinical Staph. aureus isolates being 4.70 times (95% confidence interval: 1.49, 14.75) more likely to be resistant than clinical Staph. aureus isolates. We concluded that the most common bacteria causing clinical mastitis in dairy herds in Australia is likely to be Strep. uberis, whereas Staph. aureus is likely to be the most common cause of subclinical mastitis. Despite decades of antimicrobial use to control these organisms, AMR appears to be uncommon.

Evaluation of 4 predictive algorithms for intramammary infection status in late-lactation cows.

The objective of this observational study was to compare 4 cow-level algorithms to predict cow-level intramammary infection (IMI) status (culture and MALDI-TOF) in late-lactation US dairy cows using standard measures of test performance. Secondary objectives were to estimate the likely effect of each algorithm, if used to guide selective dry cow therapy (SDCT), on dry cow antibiotic use in US dairy herds, and to investigate the importance of including clinical mastitis criteria in algorithm-guided SDCT. Cows (n = 1,594) from 56 US dairy herds were recruited as part of a previously published cross-sectional study of bedding management and IMI in late-lactation cows. Each herd was visited twice for sampling. At each farm visit, aseptic quarter-milk samples were collected from 20 cows approaching dry-off (>180 d pregnant), which were cultured using standard bacteriological methods and MALDI-TOF for identification of isolates. Quarter-level culture results were used to establish cow-level IMI status, which was considered the reference test in this study. Clinical mastitis records and Dairy Herd Improvement Association test-day somatic cell count data were extracted from herd records and used to perform cow-level risk assessments (low vs. high risk) using 4 algorithms that have been proposed for SDCT in New Zealand, the Netherlands, United Kingdom, and the United States. Agreement between aerobic culture (reference test; IMI vs. no-IMI) and algorithm status (high vs. low risk) was described using Cohen's kappa, test sensitivity, specificity, negative predictive value, and positive predictive value. The proportion of cows classified as high risk among the 4 algorithms ranged from 0.31 to 0.63, indicating that these approaches to SDCT could reduce antibiotic use at dry-off by 37 to 69% in the average US herd. All algorithms had poor agreement with IMI status, with kappa values ranging from 0.05 to 0.13. Sensitivity varied by pathogen, with higher values observed when detecting IMI caused by Streptococcus uberis, Streptococcus dysgalactiae, Staphylococcus aureus, and Lactococcus lactis. Negative predictive values were high for major pathogens among all algorithms (≥0.87), which may explain why algorithm-guided SDCT programs have been successfully implemented in field trials, despite poor agreement with overall IMI status. Removal of clinical mastitis criteria for each algorithm had little effect on the algorithm classification of cows, indicating that algorithms based on SCC alone may have similar performance to those based on SCC and clinical mastitis criteria. We recommend that producers implementing algorithm-guided SDCT use algorithm criteria that matches their relative aspirations for reducing antibiotic use (high specificity, positive predictive value) or minimizing untreated IMI at dry-off (high sensitivity, negative predictive value).

Partial budget analysis of culture- and algorithm-guided selective dry cow therapy.

The objectives of this study were to (1) use partial budget analysis to estimate the cash impact for herds that switch from blanket dry cow therapy (BDCT) to culture- or algorithm-guided selective dry cow therapy (SDCT) and (2) conduct a sensitivity analysis to investigate effects in situations where SDCT increased clinical and subclinical mastitis risk during the subsequent lactation. A partial budget model was created using Monte Carlo simulation with @Risk software. Expenditures associated with dry-off procedures and health outcomes (clinical and subclinical mastitis) during the first 30 d in milk were used to model herd-level effects, expressed in units of US dollars per cow dry-off. Values for each economic component were derived from findings from a recent multisite clinical trial, peer-reviewed journal articles, USDA databases, and our experiences in facilitating the implementation of SDCT on farms. Fixed values were used for variables expected to have minimal variation within the US dairy herd population (e.g., cost of rapid culture plates) and sampling distributions were used for variables that were hypothesized to vary enough to effect the herd net cash impact of one or more DCT approach(es). For Objective 1, herd-level udder health was assumed to be unaffected by the implementation of SDCT. For culture-guided SDCT, producers could expect to save an average of +$2.14 (-$2.31 to $7.23 for 5th and 95th percentiles) per cow dry-off as compared with BDCT, with 75.5% of iterations being ≥$0.00. For algorithm-guided SDCT, the mean net cash impact was +$7.85 ($3.39-12.90) per cow dry-off, with 100% of iterations being ≥$0.00. The major contributors to variance in cash impact for both SDCT approaches were percent of quarters treated at dry-off and the cost of dry cow antibiotics. For Objective 2, we repeated the partial budget model with the 30-d clinical and subclinical mastitis incidence increasing by 1, 2, and 5% (i.e., risk difference = 0.01, 0.02, and 0.05) in both SDCT groups compared with BDCT. For algorithm-guided SDCT, average net cash impacts were ≥$0.00 per cow dry-off (i.e., cost effective) when mastitis incidence increased slightly. However, as clinical mastitis incidence increased, economic returns for SDCT diminished. These findings indicate that when SDCT is implemented appropriately (i.e., no to little negative effect on health), it might be a cost-effective practice for US herds under a range of economic conditions.

Postcalving udder health and productivity in cows approaching dry-off with intramammary infections caused by non-aureus Staphylococcus, Aerococcus, Enterococcus, Lactococcus, and Streptococcus species.

The objective of this prospective cohort study was to explore associations between intramammary infection (IMI) in late-lactation cows and postcalving udder health and productivity. Cows (n = 2,763) from 74 US dairy herds were recruited as part of a previously published cross-sectional study of bedding management and IMI in late-lactation cows. Each herd was visited twice for sampling. At each visit, aseptic quarter milk samples were collected from 20 cows approaching dry-off (>180 d pregnant), which were cultured using standard bacteriological methods and MALDI-TOF for identification of isolates. Quarter-level culture results were used to establish cow-level IMI status at enrollment. Cows were followed from enrollment until 120 d in milk (DIM) in the subsequent lactation. Herd records were used to establish whether subjects experienced clinical mastitis or removal from the herd, and DHIA test-day data were used to record subclinical mastitis events (somatic cell count >200,000 cells/mL) and milk yield (kg/d) during the follow-up period. Cox regression and generalized estimating equations were used to evaluate the associations between IMI and the outcome of interest. The presence of late-lactation IMI caused by major pathogens was positively associated with postcalving clinical mastitis [hazard ratio = 1.5, 95% confidence interval (CI): 1.2, 2.0] and subclinical mastitis (risk ratio = 1.5, 95% CI: 1.3, 1.9). Species within the non-aureus Staphylococcus (NAS) group varied in their associations with postcalving udder health, with some species being associated with increases in clinical and subclinical mastitis in the subsequent lactation. Late-lactation IMI caused by Streptococcus and Streptococcus (Strep)-like organisms, other than Aerococcus spp. (i.e., Enterococcus, Lactococcus, and Streptococcus spp.) were associated with increases in postcalving clinical and subclinical mastitis. Test-day milk yield from 1 to 120 DIM was lower (-0.9 kg, 95% CI: -1.6, -0.3) in late-lactation cows with any IMI compared with cows without IMI. No associations were detected between IMI in late lactation and risk for postcalving removal from the herd within the first 120 DIM. Effect estimates reported in this study may be less than the underlying quarter-level effect size for IMI at dry-off and postcalving clinical and subclinical mastitis, because of the use of late-lactation IMI as a proxy for IMI at dry-off and the use of cow-level exposure and outcome measurements. Furthermore, the large number of models run in this study (n = 94) increases the chance of identifying chance associations. Therefore, confirmatory studies should be conducted. We conclude that IMI in late lactation may increase risk of clinical and subclinical mastitis in the subsequent lactation. The relationship between IMI and postcalving health and productivity is likely to vary among pathogens, with Staphylococcus aureus, Streptococcus spp., Enterococcus spp., and Lactococcus spp. being the most important pathogens identified in the current study.

Reporting radiographer peer review systems: A cross-sectional survey of London NHS Trusts.

INTRODUCTION: Peer review is frequently incorporated within radiographer reporting services. The aim of this study is to establish peer review systems used for radiograph reports provided by reporting radiographers in London. METHODS: An online cross-sectional survey of NHS diagnostic imaging departments was performed. Reporting radiographer demographics (number, frequency of reporting, scope of practice) and systems used to provide peer review of radiograph reports (review frequency, case selection, volume, outcome measure, practitioner performing the review) were collected. RESULTS: Thirteen eligible responses were received (61.9% response rate). Variability was found between Trusts in the number of reporting radiographers, frequency of reporting sessions and scope of practice. Most Trusts (9 of 13, 69.2%) have active peer review systems for radiographer reporting. All peer review systems use random case selection, most often performed on a monthly basis. Both a fixed number or a percentage of cases reported were used, with true positive, true negative, false positive, false negative the most frequent outcome measure. Of the 12 Trusts that have or are planning a peer system, all currently or plan to use reporting radiographers to conduct the review, with five (41.2%) also using consultant radiologists. CONCLUSION: Peer review of radiographer reporting is common in London NHS Trusts although there is variation in the methods used. IMPLICATIONS FOR PRACTICE: Radiographer reports frequently undergo peer review. Standardisation of reporting radiographer peer review systems should be considered, and a standardised systematic peer review system has been proposed.

Long term clinical effectiveness of ivacaftor in people with the G551D CFTR mutation.

BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, ivacaftor, was first approved for people with CF and the G551D CFTR mutation. This study describes the long-term clinical effectiveness of ivacaftor in this population. METHODS: We conducted a multicenter, prospective, longitudinal, observational study of people with CF ages ≥6 years with at least one copy of the G551D CFTR mutation. Measurements of lung function, growth, quality of life, and sweat chloride were performed after ivacaftor initiation (baseline, 1 month, 3 months, 6 months, and annually thereafter until 5.5 years). RESULTS: Ninety-six participants were enrolled, with 81% completing all study measures through 5.5 years. This cohort experienced significant improvements in percent predicted forced expiratory volume in 1 second (ppFEV1) of 4.8 [2.6, 7.1] (p < 0.001) at 1.5 years, that diminished to 0.8 [-2.0, 3.6] (p = 0.57) at 5.5 years. Adults experienced larger improvements in ppFEV1 (7.4 [3.6, 11.3], p < 0.001 at 1.5 years and 4.3 [0.6, 8.1], p = 0.02 at 5.5 years) than children (2.8 [0.1, 5.6], p = 0.04 at 1.5 years and -2.0 [-5.9, 2.0], p = 0.32 at 5.5 years). Rate of lung function decline for the overall study cohort from 1 month after ivacaftor initiation through 5.5 years was estimated to be -1.22 pp/year [-1.70, -0.73]. Significant improvements in growth, quality of life measures, sweat chloride, Pseudomonas aeruginosa detection, and pulmonary exacerbation rates requiring antimicrobial therapy persisted through five years of therapy. CONCLUSIONS: These findings demonstrate the long-term benefits and disease modifying effects of ivacaftor in children and adults with CF and the G551D mutation.

Evaluation of the urinary bladder using three-dimensional CT cinematic rendering.

Three-dimensional (3D) visualizations of volumetric data from computed tomography (CT) acquisitions can be important adjuncts to interpretation of two-dimensional (2D) reconstructions. Recently, the 3D technique known as cinematic rendering (CR) was introduced, allowing photorealistic images to be created from standard CT acquisitions. CR methodology is under increasing investigation for use in the display of regions of complex anatomy and as a tool for education and preoperative planning. In this article, we will illustrate the potential utility of CR for evaluating the urinary bladder and associated pathology. The urinary bladder is susceptible to a multitude of neoplastic and inflammatory conditions and their sequelae. The intrinsic properties of CR may prove useful for the display of subtle mucosal/luminal irregularities, the simultaneous display of soft tissue detail with high-resolution maps of associated tumor neovasculature, and the improved display of spatial relationships to aid pre-procedural planning. Further refinement of presets for CR image creation and prospective evaluation of urinary bladder CR in real-world settings will be important for widespread clinical adoption.

Multidisciplinary total eradication therapy (TET) in men with newly diagnosed oligometastatic prostate cancer.

To evaluate the outcomes of total eradication therapy (TET), designed to eradicate all sites of visible cancer and micrometastases, in men with newly diagnosed oligometastatic prostate cancer (OMPCa). Men with ≤ 5 sites of metastases were enrolled in a prospective registry study, underwent neoadjuvant chemohormonal therapy, followed by radical prostatectomy, adjuvant radiation (RT) to prostate bed/pelvis, stereotactic body radiation therapy (SBRT) to oligometastases, and adjuvant hormonal therapy (HT). When possible, the prostate-specific membrane antigen targeted 18F-DCFPyL PET/CT (18F-DCFPyL) scan was obtained, and abiraterone was added to neoadjuvant HT. Twelve men, median 55 years, ECOG 0, median PSA 14.7 ng/dL, clinical stages M0-1/12 (8%), M1a-3/12 (25%) and M1b-8/12 (67%), were treated. 18F-DCFPyL scan was utilized in 58% of cases. Therapies included prostatectomy 12/12 (100%), neoadjuvant [docetaxel 11/12 (92%), LHRH agonist 12/12 (100%), abiraterone + prednisone 6/12 (50%)], adjuvant radiation [RT 2/12 (17%), RT + SBRT 4/12 (33%), SBRT 6/12 (50%)], and LHRH agonist 12/12 (100%)]. 2/5 (40%) initial patients developed neutropenic fever (NF), while 0/6 (0%) subsequent patients given modified docetaxel dosing developed NF. Otherwise, TET resulted in no additive toxicities. Median follow-up was 48.8 months. Overall survival was 12/12 (100%). 1-, 2-, and 3-year undetectable PSA's were 12/12 (100%), 10/12 (83%) and 8/12 (67%), respectively. Median time to biochemical recurrence was not reached. The outcomes suggest TET in men with newly diagnosed OMPCa is safe, does not appear to cause additive toxicities, and may result in an extended interval of undetectable PSA.

Randomized controlled non-inferiority trial investigating the effect of 2 selective dry-cow therapy protocols on antibiotic use at dry-off and dry period intramammary infection dynamics.

Selective dry-cow therapy (SDCT) could be used to reduce antibiotic use on commercial dairy farms in the United States but is not yet widely adopted, possibly due to concerns about the potential for negative effects on cow health. The objective of this study was to compare culture- and algorithm-guided SDCT programs with blanket dry-cow therapy (BDCT) in a multi-site, randomized, natural exposure, non-inferiority trial for the following quarter-level outcomes: antibiotic use at dry-off, dry period intramammary infection (IMI) cure risk, dry period new IMI risk, and IMI risk at 1 to 13 d in milk (DIM). Two days before planned dry-off, cows in each of 7 herds were randomly allocated to BDCT, culture-guided SDCT (cult-SDCT), or algorithm-guided SDCT (alg-SDCT). At dry-off, BDCT cows received an intramammary antibiotic (500 mg of ceftiofur hydrochloride) in all 4 quarters. Antibiotic treatments were selectively allocated to quarters of cult-SDCT cows by treating only quarters from which aseptically collected milk samples tested positive on the Minnesota Easy 4Cast plate (University of Minnesota, St. Paul, MN) after 30 to 40 h of incubation. For alg-SDCT cows, antibiotic treatments were selectively allocated at the cow level, with all quarters receiving antibiotic treatment if the cow had either a Dairy Herd Improvement Association test somatic cell count >200,000 cells/mL during the current lactation or 2 or more clinical mastitis cases during the current lactation. All quarters of all cows were treated with an internal teat sealant. Intramammary infection status at enrollment and at 1 to 13 DIM was determined using standard bacteriological methods. The effect of treatment group on dry period IMI cure, dry period new IMI, and IMI risk at 1 to 13 DIM was determined using generalized linear mixed models (logistic), with marginal standardization to derive risk difference (RD) estimates. Quarter-level antibiotic use at dry-off for each group was BDCT (100%), cult-SDCT (45%), and alg-SDCT (45%). The crude dry period IMI cure risk for all quarters was 87.5% (818/935), the crude dry period new IMI risk was 20.1% (764/3,794), and the prevalence of IMI at 1 to 13 DIM was 23% (961/4,173). Non-inferiority analysis indicated that culture- and algorithm-guided SDCT approaches performed at least as well as BDCT for dry period IMI cure risk. In addition, the final models indicated that the risks for each of the 3 IMI measures were similar between all 3 treatment groups (i.e., RD estimates and 95% confidence intervals all close to 0). These findings indicate that under the conditions of this trial, culture- and algorithm-guided SDCT can substantially reduce antibiotic use at dry-off without negatively affecting IMI dynamics.

Randomized equivalence study comparing the efficacy of 2 commercial internal teat sealants in dairy cows.

The use of an internal teat sealant (ITS) at dry-off has been repeatedly shown to improve udder health in the subsequent lactation. However, almost all ITS research conducted in North America has evaluated one product (Orbeseal, Zoetis, Parsippany, NJ). The objective of this study was to evaluate a new ITS product (Lockout, Boehringer-Ingelheim Animal Health, Duluth, GA), by comparing it directly to Orbeseal in a multi-site, randomized, positively controlled equivalence trial for health indicators during the dry period [quarter-level new intramammary infection (IMI) risk, IMI cure risk, and IMI risk at 1 to 13 d in milk, DIM] and during the first 100 DIM [clinical mastitis and culling or death risk and test-day milk somatic cell count (SCC) and milk yield]. At dry-off, cows were randomly allocated to be treated with Orbeseal or Lockout after blanket administration of a cloxacillin dry cow therapy product. Cows were then followed from dry-off until 100 DIM. Intramammary infection status at enrollment and at 1 to 13 DIM was determined using standard bacteriological methods, allowing for the measurement of IMI dynamics during the dry period (i.e., IMI cures and new IMI). The effect of ITS group on dry period IMI cure, dry period new IMI, and IMI risk at 1 to 13 DIM was determined using generalized linear mixed models (logistic). Marginal standardization was used to derive risk difference estimates. An equivalence hypothesis test was conducted to compare ITS groups for dry period new IMI risk (margin of equivalence was ±5% units). The effect of ITS group on clinical mastitis and culling or death was determined using Cox proportional hazards regression. The effect of ITS group on test-day SCC and milk yield was determined using linear mixed models. Final models indicated that measures of quarter-level IMI dynamics were similar between ITS groups (i.e., risk difference estimates and 95% confidence intervals all close to zero). Furthermore, Lockout was found to be equivalent to Orbeseal for dry period new IMI risk using an equivalence hypothesis test. Hazard ratio estimates for clinical mastitis and culling or death were close to 1 and differences in SCC and milk yield between ITS groups were close to 0, indicating negligible effects of ITS group on test-day SCC and milk yield. In most cases, these effect estimates were relatively precise (i.e., narrow 95% confidence intervals). We conclude that producers using blanket dry cow therapy could consider including Orbeseal or Lockout treatment in their programs.

Randomized controlled trial investigating the effect of 2 selective dry-cow therapy protocols on udder health and performance in the subsequent lactation.

The objective of this study was to compare culture- and algorithm-guided selective dry-cow therapy (SDCT) programs with blanket dry-cow therapy (BDCT) in a multi-site, randomized, natural exposure clinical trial for the following cow-level outcomes: clinical mastitis, removal from the herd, and Dairy Herd Improvement Association (DHIA) test-day milk yield and SCC measures during the first 120 d in milk (DIM). Two days before planned dry-off, cows in each of 7 herds were randomly allocated to BDCT, culture-guided SDCT (cult-SDCT), or algorithm-guided SDCT (alg-SDCT). At dry-off, BDCT cows received an intramammary antibiotic (500 mg of ceftiofur hydrochloride) in all 4 quarters. Antibiotic treatments were selectively allocated to quarters of cult-SDCT cows by only treating quarters from which aseptically collected milk samples tested positive on a rapid culture system after 30 to 40 h of incubation. For alg-SDCT cows, antibiotic treatments were selectively allocated at the cow level, with all quarters receiving antibiotic treatment if the cow met at least one of the following criteria: (1) any DHIA test with a somatic cell count >200,000 cells/mL during the current lactation, and (2) ≥2 clinical mastitis cases during the current lactation. All quarters of all cows were treated with an internal teat sealant. Clinical mastitis and removal from the herd events (i.e., culling or death) and DHIA test-day data from dry-off to 120 DIM were extracted from herd records. Hazard ratios (HR) for the effect of treatment group on clinical mastitis and removal from the herd during 1 to 120 DIM were determined using Cox proportional hazards regression. The effects of treatment group on test-day loge-transformed SCC and milk yield were determined using linear mixed models. Final models indicated that either SDCT program was unlikely to increase clinical mastitis risk (HRcult-SDCT/BDCT = 0.82, 95% CI: 0.58, 1.15; HRalg-SDCT/BDCT = 0.83, 95% CI: 0.63, 1.09) or test-day logeSCC (cult-SDCT minus BDCT = 0.05, 95% CI: -0.09, 0.18; alg-SDCT minus BDCT = 0.07, 95% CI: -0.07, 0.21). Risk of removal from the herd and test-day milk yield were similar between treatment groups. Findings from this study indicate that culture- or algorithm-guided SDCT can be used at dry-off without negatively affecting cow health and performance in early lactation.

Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: The international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF).

BACKGROUND: Ataluren was developed for potential treatment of nonsense-mutation cystic fibrosis (CF). A previous phase 3 ataluren study failed to meet its primary efficacy endpoint, but post-hoc analyses suggested that aminoglycosides may have interfered with ataluren's action. Thus, this subsequent trial (NCT02139306) was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation CF not receiving aminoglycosides. METHODS: Eligible subjects with nonsense-mutation CF (aged ≥6 years; percent predicted (pp) FEV1 ≥40 and ≤90) from 75 sites in 16 countries were randomly assigned in double-blinded fashion to receive oral ataluren or matching placebo thrice daily for 48 weeks. The primary endpoint was absolute change in average ppFEV1 from baseline to the average of Weeks 40 and 48. FINDINGS: 279 subjects were enrolled; 138 subjects in the ataluren arm and 136 in the placebo arm were evaluable for efficacy. Absolute ppFEV1 change from baseline did not differ significantly between the ataluren and placebo groups at Week 40 (-0.8 vs -1.8) or Week 48 (-1.7 vs -2.4). Average ppFEV1 treatment difference from baseline to Weeks 40 and 48 was 0.6 (95% CI -1.3, 2.5; p = 0.54). Pulmonary exacerbation rate per 48 weeks was not significantly different (ataluren 0.95 vs placebo 1.13; rate ratio p = 0.40). Safety was similar between groups. No life-threatening adverse events or deaths were reported. INTERPRETATION: Neither ppFEV1 change nor pulmonary exacerbation rate over 48 weeks were statistically different between ataluren and placebo groups. Development of a nonsense-mutation CF therapy remains elusive.