Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease

The methionine (M)-valine (V) polymorphic codon 129 of the prion protein gene (PRNP) plays a central role in both susceptibility and phenotypic expression of sporadic Creutzfeldt-Jakob diseases (sCJD). Experimental transmissions of sCJD in humanized transgenic mice led to the isolation of five prion strains, named M1, M2C, M2T, V2, and V1, based on two major conformations of the pathological prion protein (PrPSc, type 1 and type 2), and the codon 129 genotype determining susceptibility and propagation efficiency. While the most frequent sCJD strains have been described in codon 129 homozygosis (MM1, MM2C, VV2) and heterozygosis (MV1, MV2K, and MV2C), the V1 strain has only been found in patients carrying VV. We identified six sCJD cases, 4 in Catalonia and 2 in Italy, carrying MV at PRNP codon 129 in combination with PrPSc type 1 and a new clinical and neuropathological profile reminiscent of the VV1 sCJD subtype rather than typical MM1/MV1. All patients had a relatively long duration (mean of 20.5 vs. 3.5 months of MM1/MV1 patients) and lacked electroencephalographic periodic sharp-wave complexes at diagnosis. Distinctive histopathological features included the spongiform change with vacuoles of larger size than those seen in sCJD MM1/MV1, the lesion profile with prominent cortical and striatal involvement, and the pattern of PrPSc deposition characterized by a dissociation between florid spongiform change and mild synaptic deposits associated with coarse, patch-like deposits in the cerebellar molecular layer. Western blot analysis of brain homogenates revealed a PrPSc type 1 profile with physicochemical properties reminiscent of the type 1 protein linked to the VV1 sCJD subtype. In summary, we have identified a new subtype of sCJD with distinctive clinicopathological features significantly overlapping with those of the VV1 subtype, possibly representing the missing evidence of V1 sCJD strain propagation in the 129MV host genotype

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

A Five-day Progesterone plus eCG-based Fixed-time AI Protocol Improves Fertility over Spontaneous Estrus in High-producing Dairy Cows under Heat Stress.

This study compared the efficiency of a five-day or standard (nine-day) progesterone-based 4 regimen combined with equine chorionic gonadotrophin (eCG) in a fixed-time AI (FTAI) 5 protocol for dairy cows. The data examined were derived from 3577 inseminations conducted in 6 three dairy herds. Animals with no estrus signs detected over 21 days were randomly assigned 7 to a PRID-9 or PRID-5 group. Cows in each group received a progesterone intravaginal device 8 (PRID) for 9 or 5 days, respectively, PGF2α and eCG on PRID removal, and GnRH 48 hours 9 later. Fixed-time AI was performed 12 hours after the GnRH dose. Cows artificially 10 inseminated following spontaneous estrus during the study period were considered as controls. 11 Based on the odds ratio, the likelihoods of animals in PRID-9 in the warm (conception 12 rate [CR] of 22.3%) and cool (32% CR) periods, and control animals in the warm period 13 (26.6% CR) becoming pregnant were reduced (by factors of 0.6, 0.3 and 0.4, 14 respectively) compared with the control animals in the cool period (CR of 43.7%). The 15 risk of a twin pregnancy was higher (51.4%) for cystic PRID-9 cows (by a factor of 3.6) 16 and lower (9.9%) for cyclic PRID-5 animals (by a factor of 0.4) compared with the 17 PRID-9 cyclic cows. These findings indicate that the proposed protocol achieves similar 18 results during the cool or warm season to those obtained when AI is conducted at spontaneous 19 estrus during the cool season. In addition, PRID-5 reduced twin pregnancy compared with 20 PRID-9

Nutrient Prioritization in Dairy Cows Early Postpartum: Mismatch Between Metabolism and Fertility

For several decades, researchers worldwide report a decrease in fertility in high-yielding dairy cows, most probably based on conflicting metabolic and reproductive needs. The dairy herd manager's success at improving milk production has been accompanied by a negative trend for the most visible reproductive parameters such as calving intervals, number of days open and number of inseminations needed per pregnancy. In parallel, many research groups studied the metabolic and endocrine factors that influence follicular growth and the developmental competence of oocytes and embryos. In the past, herd managers and reproductive biologists each tried to tackle the same problems with limited consultation. More recently, the situation has improved significantly and theriogenologists, nutritionists and veterinarians now conduct research in multidisciplinary teams. This review paper starts in a general way by discussing nutrient prioritization towards the udder to guarantee milk production and by describing interactions between the somatotropic and gonadotropic axis. It then focuses on the consequences of the negative energy balance on follicular growth and environment, oocyte and embryo quality, not only by summarizing the currently accepted hypotheses but also based on clear scientific evidence at the follicular level. All this, with one question in mind: is there a mismatch between metabolism and fertility and what can the dairy manager learn from research to tackle the problem of reduced fertility

Transfer of a single fresh in vitro-produced embryo may prevent twin pregnancy without compromising the fertility of the cow

This study examines whether the transfer of a fresh in vitro-produced (IVP) embryo can avoid the risk of twin pregnancy without reducing the fertility of a cow. The study population was comprised of 416 lactating dairy cows synchronized for oestrus: 294 were fixed-time inseminated (AI cows), and 122 were given GnRH treatment at the time of embryo transfer (ET) an IVP embryo (ET cows). Of the 416 cows, 167 (40.1%) became pregnant. Twin pregnancy was recorded in 20.8% of the AI pregnant cows (21/101), whereas no ET cows had twins (0/66). Significant interaction (p <.01) was observed between breeding technique and the period of the year for the likelihood of pregnancy. This meant that using AI cows during the warm period (May–September) as reference, the odds ratio for pregnancy in ET cows during the warm period was 3.4 (p =.001). In conclusion, transfer of a single fresh IVP embryo proved useful to prevent the risk of twin pregnancy without affecting fertility