Measuring lameness prevalence: effects of case definition and assessment frequency

Lameness assessments are commonly conducted at a single point in time, but such assessments are subject to multiple sources of error. We conducted a longitudinal study, assessing the gait of 282 lactating dairy cows weekly during the first 12 wk of lactation, with the aim of assessing how lameness prevalence changed in relation to case definition and assessment frequency. Gait was scored using a 5-point scale where scores of 1 and 2 were considered sound, 3 was clinically lame, and 4 and 5 were severely lame. We created 5 lameness definitions using increasingly stringent thresholds based upon the number of consecutive events of locomotion score ≥3. In LAME1, a cow was considered lame when locomotion score was ≥3 at any scoring event, in LAME2, LAME3, LAME4, and LAME5, a cow was considered lame when locomotion score was 3 or higher during 2, 3, 4, and 5 consecutive scoring events, respectively. We also assessed the effect of assessment frequency on measures of prevalence and incidence using weekly assessment (ASSM1), 1 assessment every 2 wk (ASSM2), 1 assessment every 3 wk (ASSM3), and 1 assessment every 4 wk (ASSM4). Using LAME1, 69.2% of cows were considered lame at some point during the trial, with an average point prevalence of 31.8% (SD: 2.8) and average incidence rate of 10.9 cases/100 cow weeks (SD: 3.7). Lameness prevalence decreased to 28.0% when using LAME5. Survival analysis was used to assess the effects of parity, using these different case definitions. Parity is a known risk for lameness, such that case definitions and prevalence estimates should be stratified by parity to inform management decisions. Using the LAME3 criterion, primiparous cows had the highest chance of reaching 12 wk without a lameness event, and fourth and higher parities had the lowest. Weighted linear and quadratic kappa values were used to assess agreement between different assessment frequencies and lameness definitions; we found substantial to excellent agreement between ASSM1 and ASSM2 using LAME1, LAME2, and LAME3 definitions. Agreement was fair to substantial between ASSM1 and ASSM3 and low to fair between ASSM1 and ASSM4. Likewise, the agreement between LAME1 and LAME2 was fair in primiparous cows, substantial in second and third parity cows, and poor to fair in fourth and greater parity cows. We conclude that lameness prevalence estimates are dependent upon case definition and that the use of more stringent case definitions results in fewer cows classified as lame. These results suggest that routine locomotion assessments be conducted at least every 2 wk, and that cows should be defined as lame on the basis of 2 consecutive assessments

Cemiplimab in locally advanced or metastatic cutaneous squamous cell carcinoma:prospective real-world data from the DRUG Access Protocol

Background: The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC). Methods: Patients with laCSCC or mCSCC received cemiplimab 350 mg fixed dose every three weeks. Primary endpoints were objective clinical benefit rate (CBR), defined as objective response (OR) or stable disease (SD) at 16 weeks, physician-assessed CBR, defined as clinician's documentation of improved disease or SD based on evaluation of all available clinical parameters at 16 weeks, objective response rate (ORR), and safety, defined as grade ≥ 3 treatment related adverse events (TRAEs) occurring up to 30 days after last drug administration. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Findings: Between February 2021 and December 2022, 151 patients started treatment. Objective and physician-assessed CBR were 54.3% (95% CI, 46.0–62.4) and 59.6% (95% CI, 51.3–67.5), respectively. ORR was 35.1% (95% CI, 27.5–43.3). After a median follow-up of 15.2 months, median DoR was not reached. Median PFS and OS were 12.2 (95% CI, 7.0-not reached) and 24.2 months (95% CI, 18.8-not reached), respectively. Sixty-eight TRAEs occurred in 29.8% of patients. Most commonly reported TRAE was a kidney transplant rejection (9.5%). Interpretation: Cemiplimab proved highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice. Funding: The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Janssen, Lilly, Merck, Novartis, Roche, and Sanofi.</p

PCM4EU and PRIME-ROSE:Collaboration for implementation of precision cancer medicine in Europe

Background: In the two European Union (EU)-funded projects, PCM4EU (Personalized Cancer Medicine for all EU citizens) and PRIME-ROSE (Precision Cancer Medicine Repurposing System Using Pragmatic Clinical Trials), we aim to facilitate implementation of precision cancer medicine (PCM) in Europe by leveraging the experience from ongoing national initiatives that have already been particularly successful. Patients and methods: PCM4EU and PRIME-ROSE gather 17 and 24 partners, respectively, from 19 European countries. The projects are based on a network of Drug Rediscovery Protocol (DRUP)-like clinical trials that are currently ongoing or soon to start in 11 different countries, and with more trials expected to be established soon. The main aims of both the projects are to improve implementation pathways from molecular diagnostics to treatment, and reimbursement of diagnostics and tumour-tailored therapies to provide examples of best practices for PCM in Europe. Results: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu. eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. Conclusion: European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients.</p

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

Cemiplimab in locally advanced or metastatic cutaneous squamous cell carcinoma:prospective real-world data from the DRUG Access Protocol

Background: The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC).Methods: Patients with laCSCC or mCSCC received cemiplimab 350 mg fixed dose every three weeks. Primary endpoints were objective clinical benefit rate (CBR), defined as objective response (OR) or stable disease (SD) at 16 weeks, physician-assessed CBR, defined as clinician's documentation of improved disease or SD based on evaluation of all available clinical parameters at 16 weeks, objective response rate (ORR), and safety, defined as grade ≥ 3 treatment related adverse events (TRAEs) occurring up to 30 days after last drug administration. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS).Findings: Between February 2021 and December 2022, 151 patients started treatment. Objective and physician-assessed CBR were 54.3% (95% CI, 46.0–62.4) and 59.6% (95% CI, 51.3–67.5), respectively. ORR was 35.1% (95% CI, 27.5–43.3). After a median follow-up of 15.2 months, median DoR was not reached. Median PFS and OS were 12.2 (95% CI, 7.0-not reached) and 24.2 months (95% CI, 18.8-not reached), respectively. Sixty-eight TRAEs occurred in 29.8% of patients. Most commonly reported TRAE was a kidney transplant rejection (9.5%). Interpretation: Cemiplimab proved highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice.Funding: The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Janssen, Lilly, Merck, Novartis, Roche, and Sanofi.</p

Positron emission tomography for serial imaging of the contused adult rat spinal cord.

Item does not contain fulltextWe investigated whether small-animal positron emission tomography (PET) could be used in combination with computed tomography (CT) imaging techniques for longitudinal monitoring of the injured spinal cord. In adult female Sprague-Dawley rats (n = 6), the ninth thoracic (T9) spinal cord segment was exposed by laminectomy and subsequently contused using the Infinite Horizon impactor (Precision System and Instrumentation, Lexington, KY) at 225 kDyn. In control rats (n = 4), the T9 spinal cord was exposed by laminectomy but not contused. At 0.5 hours and 3, 7, and 21 days postinjury, 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) was given intravenously followed 1 hour later by sequential PET and CT. Regions of interest (ROIs) at T9 (contused) and T6 (uninjured) spinal cord segments were manually defined on CT images and aided by fiduciary markers superimposed onto the coregistered PET images. Monte Carlo simulation revealed that about 33% of the activity in the ROIs was due to spillover from adjacent hot areas. A simulation-based partial-volume compensation (PVC) method was developed and used to correct for this spillover effect. With PET-CT, combined with PVC, we were able to serially measure standardized uptake values of the T9 and T6 spinal cord segments and reveal small, but significant, differences. This approach may become a tool to assess the efficacy of spinal cord repair strategies.1 april 201

PCM4EU and PRIME-ROSE: Collaboration for implementation of precision cancer medicine in Europe

&lt;p class="p1"&gt;&lt;strong&gt;Background: &lt;/strong&gt;In the two European Union (EU)-funded projects, PCM4EU (Personalized Cancer Medicine for all EU citizens) and PRIME-ROSE (Precision Cancer Medicine Repurposing System Using Pragmatic Clinical Trials), we aim to facilitate implementation of precision cancer medicine (PCM) in Europe by leveraging the experience from ongoing national initiatives that have already been particularly successful.&lt;/p&gt;&lt;p class="p1"&gt;&lt;strong&gt;Patients and methods: &lt;/strong&gt;PCM4EU and PRIME-ROSE gather 17 and 24 partners, respectively, from 19 European countries. The projects are based on a network of Drug Rediscovery Protocol (DRUP)-like clinical trials that are currently ongoing or soon to start in 11 different countries, and with more trials expected to be established soon. The main aims of both the projects are to improve implementation pathways from molecular diagnostics to treatment, and reimbursement of diagnostics and tumour-tailored therapies to provide examples of best practices for PCM in Europe.&lt;/p&gt;&lt;p class="p1"&gt;&lt;strong&gt;Results: &lt;/strong&gt;PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (&lt;span class="s1"&gt;http://www.pcm4eu.eu&lt;/span&gt;). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024.&lt;/p&gt;&lt;p class="p1"&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients.&lt;/p&gt