E. coli monothiol glutaredoxin GrxD replenishes Fe-S clusters to the essential ErpA A-type carrier under low iron stress.

Iron-sulfur (Fe-S) clusters are required for essential biological pathways, including respiration and isoprenoid biosynthesis. Complex Fe-S cluster biogenesis systems have evolved to maintain an adequate supply of this critical protein cofactor. In Escherichia coli, two Fe-S biosynthetic systems, the "housekeeping" Isc and "stress responsive" Suf pathways, interface with a network of cluster trafficking proteins, such as ErpA, IscA, SufA, and NfuA. GrxD, a Fe-S cluster-binding monothiol glutaredoxin, also participates in Fe-S protein biogenesis in both prokaryotes and eukaryotes. Previous studies in E. coli showed that the ΔgrxD mutation causes sensitivity to iron depletion, spotlighting a critical role for GrxD under conditions that disrupt Fe-S homeostasis. Here, we utilized a global chemoproteomic mass spectrometry (MS) approach to analyse the contribution of GrxD to the Fe-S proteome. Our results demonstrate that 1) GrxD is required for biogenesis of a specific subset of Fe-S proteins under iron-depleted conditions, 2) GrxD is required for cluster delivery to ErpA under iron limitation, 3) GrxD is functionally distinct from other Fe-S trafficking proteins and, 4) GrxD Fe-S cluster binding is responsive to iron limitation. All these results lead to the proposal that GrxD is required to maintain Fe-S cluster delivery to the essential trafficking protein ErpA during iron limitation conditions.

Assessing Functional Outcomes of Partial Versus Radical Nephrectomy for T1b-T2 Renal Masses: Results from a Multi-institutional Collaboration.

BACKGROUND: Deterioration of renal function is associated with increased all-cause mortality. In renal masses larger than 4 cm, whether partial versus radical nephrectomy (PN vs. RN) might affect long-term functional outcomes is unknown. This study tested the association between PN versus RN and postoperative acute kidney injury (AKI), recovery of at least 90% of the preoperative estimated glomerular filtration rate (eGFR) at 1 year, upstaging of chronic kidney disease (CKD) one stage or more at 1 year, and eGFR decline of 45 ml/min/1.73 m2 or less at 1 year. METHODS: Data from 23 high-volume institutions were used. The study included only surgically treated patients with single, unilateral, localized, clinical T1b-2 renal masses. Multivariable logistic regression analyses were performed. RESULTS: Overall, 968 PN patients and 325 RN patients were identified. The rate of AKI was lower in the PN versus the RN patients (17% vs. 58%; p < 0.001). At 1 year after surgery, for the PN versus the RN patients, the rate for recovery of at least 90% of baseline eGFR was 51% versus 16%, the rate of CKD progression of ≥ 1 stage was 38% versus 65%, and the rate of eGFR decline of 45 ml/min/1.73 m2 or less was 10% versus 23% (all p < 0.001). Radical nephrectomy independently predicted AKI (odds ratio [OR], 7.61), 1-year ≥ 90% eGFR recovery (OR, 0.30), 1-year CKD upstaging (OR, 1.78), and 1-year eGFR decline of 45 ml/min/1.73 m2 or less (OR, 2.36) (all p ≤ 0.002). CONCLUSIONS: For cT1b-2 masses, RN portends worse immediate and 1-year functional outcomes. When technically feasible and oncologically safe, efforts should be made to spare the kidney in case of large renal masses to avoid the hazard of glomerular function loss-related mortality.

Ex Vivo Herpes Simplex Virus Reactivation Involves a Dual Leucine Zipper Kinase-Dependent Wave of Lytic Gene Expression That Is Independent of Histone Demethylase Activity and Viral Genome Synthesis.

Herpes simplex virus 1 (HSV-1) maintains a lifelong latent infection in neurons and periodically reactivates, resulting in the production of infectious virus. The exact cellular pathways that induce reactivation are not understood. In primary neuronal models of HSV latency, the cellular protein dual leucine zipper kinase (DLK) has been found to initiate a wave of viral gene expression known as phase I. Phase I occurs independently of both viral DNA replication and the activities of histone demethylase enzymes required to remove repressive heterochromatin modifications associated with the viral genome. In this study, we investigated whether phase I-like gene expression occurs in ganglia reactivated from infected mice. Using the combined trigger of explant-induced axotomy and inhibition of phosphatidylinositide 3-kinase (PI3K) signaling, we found that HSV lytic gene expression was induced rapidly from both sensory and sympathetic neurons. Ex vivo reactivation involved a wave of viral late gene expression that occurred independently of viral genome synthesis and histone demethylase activity and preceded the detection of infectious virus. Importantly, we found that DLK was required for the initial induction of lytic gene expression. These data confirm the essential role of DLK in inducing HSV-1 gene expression from the heterochromatin-associated genome and further demonstrate that HSV-1 gene expression during reactivation occurs via mechanisms that are distinct from lytic replication. IMPORTANCE Reactivation of herpes simplex virus from a latent infection is associated with clinical disease. To develop new therapeutics that prevent reactivation, it is important to understand how viral gene expression initiates following a reactivation stimulus. Dual leucine zipper kinase (DLK) is a cellular protein that has previously been found to be required for HSV reactivation from sympathetic neurons in vitro. Here, we show that DLK is essential for reactivation from sensory ganglia isolated from infected mice. Furthermore, we show that DLK-dependent gene expression ex vivo occurs via mechanisms that are distinct from production replication, namely, lytic gene expression that is independent of viral DNA replication and histone demethylase activity. The identification of a DLK-dependent wave of lytic gene expression from sensory ganglia will ultimately permit the development of novel therapeutics that target lytic gene expression and prevent the earliest stage of reactivation.

Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET.

INTRODUCTION: HGF/c-MET signaling is a significant driver of glioblastoma (GBM) growth and disease progression. Unfortunately, c-MET targeted therapies have been found to be largely ineffective suggesting additional redundant mechanisms of c-MET activation. METHODS: Utilizing RNA-sequencing (RNA-seq) and ribosome profiling analyses of circular RNAs, circ-HGF (hsa_circ_0080914) was identified as markedly upregulated in primary GBM and found to potentially encode an HGF protein variant (C-HGF) 119 amino acids in length. This candidate HGF variant was characterized and evaluated for its ability to mediate c-MET activation and regulate PDX GBM cell growth, motility and invasive potential in vitro and tumor burden in intracranial xenografts in mice. RESULTS: An internal ribosome entry site (IRES) was identified within the circ-HGF RNA which mediated translation of the cross-junctional ORF encoding C-HGF and was observed to be highly expressed in GBM relative to normal brain tissue. C-HGF was also found to be secreted from GBM cells and concentrated cell culture supernatants or recombinant C-HGF activated known signaling cascades downstream of c-MET. C-HGF was shown to interact directly with the c-MET receptor resulting in its autophosphorylation and activation in PDX GBM lines. Knockdown of C-HGF resulted in suppression of c-MET signaling and marked inhibition of cell growth, motility and invasiveness, whereas overexpression of C-HGF displayed the opposite effects. Additionally, modulation of C-HGF expression regulated tumor growth in intracranial xenografted PDX GBM models. CONCLUSIONS: These results reveal an alternative mechanism of c-MET activation via a circular RNA encoded HGF protein variant which is relevant in GBM biology. Targeting C-HGF may offer a promising approach for GBM clinical management.

One-year healthcare costs after robotic-assisted and laparoscopic partial and radical nephrectomy: a cohort study.

OBJECTIVE: Despite the wide-spread adoption of robotic-assisted surgery (RAS), the cost-benefit implications for partial (PN) and radical nephrectomy (RN) versus laparoscopic surgery (Lap) is not well established. We sought to examine the trend of adoption and 1-year healthcare expenditure of PN and RN, and compare 1-year expenditures of RAS versus Lap for PN and RN. PATIENTS AND METHODS: This cohort study used the MerativeTM MarketScan® Databases between 2013 and 2020. A total of 5,353 patients with kidney cancer undergoing PN (2,980, 55.7%) or RN (2,373, 44.3%). We compared open-conversion, length of stay (LOS), index expenditure, 1-year healthcare expenditure and utilization, and missed work-days between RAS and Lap for PN and RN. RESULTS: Adoption of PN increased overtime (47.0% to 55.8%), mainly driven by robotic PN increase. Among PN, RAS had lower open-conversion, shorter LOS and lower index expenditure than Lap. Among RN, RAS had shorter LOS, and similar open-conversion and index expenditures. During 1-year post-discharge, RAS had lower hospital outpatient visits (IRR = 0.92, 95% CI = 0.85, 0.99, p = 0.029) and office-based visits (IRR = 0.91, 95% CI = 0.86, 0.96, p = 0.002) for PN, translating to a 1-day less (95% CI = 0.25, 1.75, p = 0.008) missed from work for RAS. Following RN, RAS had lower 1-year readmission than Lap (O.R = 0.72, 95% CI = 0.55, 0.94, p = 0.018). RAS and Lap had comparable 1-year post-discharge expenditures for both PN (mean difference, MD = -$475, 95% CI = -$4362, $3412, p = 0.810) and RN (MD = -$4,204, 95% CI = -$13,837, $5430, p = 0.404). CONCLUSION: At index surgery, RAS was associated with shorter LOS for both PN and RN, and lower open-conversion and expenditures for PN. RAS and Lap had comparable 1-year total expenditures, despite lower healthcare visits for RAS.

Effects of increased grazing intensity during the early and late grazing periods on the welfare of spring-calving, pasture-based dairy cows.

The objective of this study was to identify potential effects of increased grazing intensity, characterized by differing pasture availability and stocking rate, on indicators of welfare during both early and late grazing periods. Seventy spring-calving, pasture-based Holstein-Friesian and cross-bred dairy cows, averaging 35 ± 16 d in milk on the first day of data collection, were assigned to 3 treatments (20-26 cows/treatment) representing a range in grazing intensity: LO (high pasture availability, 980 kg DM/ha opening cover, 2.75 cows/ha, 90:10% pasture:concentrate diet), MOD (medium pasture availability, 720 kg DM/ha opening cover, 2.75 cows/ha, 90:10% pasture:concentrate diet), and HI (low pasture availability, 570 kg DM/ha opening cover, 3.25 cows/ha, 80:20% pasture:concentrate diet); representative of current, best practice and proposed production levels respectively for this system. Welfare indicators were locomotion score, digital dermatitis and white line disease, rumen fill, ocular and nasal discharge, integument damage to the neck-back and hock regions, and lying time. Data were collected during a 5-wk early grazing period in spring (EG) and a 7-wk late grazing period in autumn (LG). Average daily lying time was recorded for 8 to 10 focal cows per treatment. Results demonstrated only minor treatment effects. Cows on MOD [odds ratio (OR) = 3.11] and HI (OR = 1.95) were more likely to display nasal discharge compared with LO. Cows on MOD tended to have more damage to the skin on the neck-back region than LO (OR = 4.26). Total locomotion score (maximum = 25) was greater on LOW (7.1 ± 0.20) compared with HI (6.5 ± 0.19). Average lame cow prevalence for EG and LG respectively was 15.3 ± 3.12% and 39.2 ± 3.00% (LO), 20.0 ± 2.58% and 24.2 ± 5.69% (MOD), and 14.9 ± 4.79% and 17.0 ± 3.44% (HI). Cows on HI were less likely to have impaired walking speed than either LO (OR = 0.24) or MOD (OR = 0.29). Cows on both HI (OR = 0.36) and MOD (OR = 0.40) were less likely to display impaired abduction or adduction compared with those on LO. An interaction between treatment and period revealed longer lying times for cows on LO (10.6 h/d ± 0.39) compared with both MOD and HI (8.7 ± 0.43 and 8.4 ± 0.41 h/d) during EG only. The greatest effects were across grazing periods, with all indicators except rumen fill and locomotion score demonstrating improvements from EG to LG. This suggests cows were able to cope well with increasing levels of grazing intensity, and that regardless of treatment, a greater number of days on pasture led to improvements in welfare indicators.

Cow- and herd-level risk factors for lameness in partly housed pasture-based dairy cows.

Lameness in dairy cows is a major animal welfare concern and has substantial economic impact through reduced production and fertility. Previous risk factor analyses have focused on housed systems, rather than those where cows were grazed for the majority of the year and housed only for the winter period. Therefore, the aim of this observational study was to identify a robust set of cow-level and herd-level risk factors for lameness in a pasture-based system, based on predictors from the housing and grazing periods. Ninety-nine farms were visited during the grazing period (April 2019-September 2019), and 85 farms were revisited during the housing period (October 2019-February 2020). At each visit, all lactating cows were scored for lameness (0 = good mobility, 1 = imperfect mobility, 2 = impaired mobility, 3 = severely impaired mobility), and potential herd-level risk factors were recorded through questionnaires and infrastructure measurements. Routine cow-level management data were also collected. Important risk factors for lameness were derived though triangulation of results from elastic net regression, and from logistic regression model selection using modified Bayesian information criterion. Both selection methods were implemented using bootstrapping. This novel approach has not previously been used in a cow-level or herd-level risk factor analysis in dairy cows, to the authors' knowledge. The binary outcome variable was lameness status, whereby cows with a lameness score of 0 or 1 were classed as non-lame and cows with a score of 2 or 3 were classed as lame. Cow-level risk factors for increased lameness prevalence were age and genetic predicted transmitting ability for lameness. Herd-level risk factors included farm and herd size, stones in paddock gateways, slats on cow tracks near the collecting yard, a sharper turn at the parlor exit, presence of digital dermatitis on the farm, and the farmers' perception of whether lameness was a problem on the farm. This large-scale study identified the most important associations between risk factors and lameness, based on the entire year (grazing and housing periods), providing a focus for future randomized clinical trials.

Effect of feeding single-dam or pooled colostrum on maternally derived immunity in dairy calves.

The role of colostrum management in providing adequate immunological protection to neonatal calves has been widely investigated, and thresholds for colostrum quality, as well as optimum volume and timing for colostrum feeding have been established. However, limited information is available on the effect of colostrum source (single dam or pooled) on passive immunity, as well as subsequent antibody survival in the calf. This study aimed to assess the effect of feeding single-dam colostrum (own and other dam) or pooled colostrum on transfer of passive immunity, and also investigate the rate of depletion of disease-specific antibodies among dairy calves. In total, 320 cows and 119 dairy heifer calves were enrolled in the study. Calves were blood-sampled immediately after birth and received either own-dam, other-dam, or pooled colostrum. Calves were blood-sampled at 24 h to assess serum IgG concentrations and at monthly intervals thereafter to document disease-specific antibody survival. Mean colostrum IgG concentration was higher for other-dam treatment group, whereas own-dam and pooled treatments were similar. For all treatment groups, the mean IgG concentration was >80 mg/mL, exceeding the quality threshold of 50 mg/mL. Mean calf serum IgG concentration was lower for calves fed pooled colostrum compared with those that received colostrum from a single cow. There was a negative association with 24-h serum IgG and calf birth bodyweight; calves <30 kg at birth had the highest 24-h serum IgG concentration. Survival of antibodies to bovine viral diarrhea, Salmonella infection, leptospirosis, bovine parainfluenza 3 virus, bovine respiratory syncytical virus, rotavirus, and coronavirus was not associated with colostrum source; however, antibodies to infectious bovine rhinotracheitis had a greater period of survival among calves fed own-dam colostrum. We found that feeding single-dam colostrum can thus improve calf immunity through increased serum IgG levels and antibody survival rates. Furthermore, we hypothesize that immune exclusion may occur with pooled colostrum; therefore, providing pooled colostrum may still be a good practice as long as it can be ensured that enough antibodies are absorbed into the blood stream to deal with pathogens calves may encounter because different dams may have antibodies against different strains of viruses and bacteria, yielding cross protection.

Patient engagement study to identify and improve surgical experience.

BACKGROUND: Patient engagement is the establishment of active partnerships between patients, families, and health professionals to improve healthcare delivery. The objective of this project was to conduct a series of patient engagement workshops to identify areas to improve the surgical experience and develop strategies to address areas identified as high priority. METHODS: Faculty surgeons and patients were invited to participate in three in-person meetings. Evaluation included identifying and developing strategies for three priority areas to improve the surgical experience and level of engagement achieved at each meeting. RESULTS: Sixteen faculty surgeons and 32 patients participated. Some 63 themes to improve the surgical experience were identified; the three highest-priority themes were physician communication, discharge process, and expectations at home after discharge. Individual improvement strategies for these three prioritized themes (12, 36 and 6 respectively) were used to develop a formal strategic plan, and included a physician communication survey, discharge process worksheet and video, and guideline regarding what to expect at home after discharge. Overall, the level of engagement achieved was considered high by over 85 per cent of the participants. CONCLUSION: A high level of patient engagement was achieved. Priorities were identified with patients and surgeons to improve surgical experience, and strategies were developed to address these areas.

Association between chronic kidney disease and COVID-19-related mortality in New York.

PURPOSE: To evaluate mortality risk of CKD patients infected with COVID-19, and assess shared characteristics associated with health disparities in CKD outcome. METHODS: We extracted the data from a case series of 7624 patients presented at Mount Sinai Health System, in New York for testing between 3/28/2020 and 4/16/2020. De-identified patient data set is being produced by the Scientific Computing department and made available to the Mount Sinai research community at the following website: https://msdw.mountsinai.org/ . RESULTS: Of 7624 COVID-19 patients, 7.8% (n = 597) had CKD on hospital admission, and 11.2% (n = 856) died of COVID-19 infection. CKD patients were older, more likely to have diabetes, hypertension, and chronic obstructive pulmonary disease (COPD), were current or former smokers, had a longer time to discharge, and had worse survival compared to non-CKD patients (p < 0.05). COVID-19 mortality rate was significantly higher in CKD patients (23.1% vs 10.2%) with a 1.51 greater odds of dying (95% CI: 1.19-1.90). Controlling for demographic, behavioral, and clinical covariates, the logistic regression analysis showed significant and consistent effects of CKD, older age, male gender, and hypertension with mortality (p < 0.05). CONCLUSION: CKD was a significant independent predictor of COVID-19 mortality, along with older age, male gender, and hypertension. Future research will investigate the effects of COVID-19 on long-term renal function.

Children are safe in schools: a review of the Irish experience of reopening schools during the COVID-19 pandemic.

OBJECTIVES: Schools in the Republic of Ireland reopened to students and staff in late August 2020. We sought to determine the test positivity rate of close contacts of cases of coronavirus disease 2019 (COVID-19) in schools during the first half-term of the 2020/2021 academic year. METHODS: National-level data from the schools' testing pathway were interrogated to determine the positivity rate of close contacts of cases of COVID-19 in Irish primary, postprimary and special schools during the first half-term of 2020/2021 academic year. The positivity rates among adult and child close contacts were compared and the proportion of national cases of COVID-19 who were aged 4-18 years during the observation period was calculated to assess whether this proportion increased after schools reopened. RESULTS: Of all, 15,533 adult and child close contacts were tested for COVID-19 through the schools' testing pathway during the first half-term of the 2020/2021 academic year. Three hundred and ninety-nine close contacts tested positive, indicating a positivity rate of 2.6% (95% confidence interval: 2.3-2.8%). The positivity rates of child and adult close contacts were similarly low (2.6% vs 2.7%, P = 0.7). The proportion of all national cases of COVID-19 who were aged 4-18 years did not increase during the first half-term of the 2020/2021 school year. CONCLUSIONS: The low positivity rate of close contacts of cases of COVID-19 in schools indicate that transmission of COVID-19 in Irish schools during the first half-term of the 2020/2021 academic year was low. These findings support policies to keep schools open during the pandemic.

Selective clamping during robot-assisted partial nephrectomy in patients with a solitary kidney: is it safe and does it help?

OBJECTIVES: To obtain the most accurate assessment of the risks and benefits of selective clamping in robot-assisted partial nephrectomy (RAPN) we evaluated outcomes of this technique vs those of full clamping in patients with a solitary kidney undergoing RAPN. PATIENTS AND METHODS: Data from institutional review board-approved retrospective and prospective databases from 2006 to 2019 at multiple institutions with sharing agreements were evaluated. Patients with a solitary kidney were identified and stratified based on whether selective or full renal artery clamping was performed. Both groups were analysed with regard to demographics, risk factors, intra-operative complications, and postoperative outcomes using chi-squared tests, Fisher's exact tests, t-tests and Mann-Whitney U-tests. RESULTS: Our initial cohort consisted of 4112 patients, of whom 72 had undergone RAPN in a solitary kidney (51 with full clamping and 21 with selective clamping). There were no significant differences in demographics, tumour size, baseline estimated glomerular filtration rate (eGFR), or warm ischaemia time (WIT) between the groups (Table 1). Intra-operative outcomes, including estimated blood loss, operating time, and intra-operative complications were similar in the two groups. Short- and long-term postoperative percentage change in eGFR, frequency of acute kidney injury (AKI), and frequency of de novo chronic kidney disease (CKD) were also not significantly different between the two techniques. CONCLUSION: In a large cohort of patients with solitary kidney undergoing RAPN, selective clamping resulted in similar intra-operative and postoperative outcomes compared to full clamping and conferred no additional risk of harm. However, selective clamping did not appear to provide any functional advantage over full clamping as there was no difference observed in the frequency of AKI, CKD or change in eGFR. Short WIT in both groups (<15 min) may have prevented identification of benefits in the selective clamping group; a similar study analysing cases with longer WIT may elucidate any beneficial effects of selective clamping.

Do patients with Stage 3-5 chronic kidney disease benefit from ischaemia-sparing techniques during partial nephrectomy?

OBJECTIVE: To analyse whether selective arterial clamping (SAC) and off-clamp (OC) techniques during robot-assisted partial nephrectomy (RPN) are associated with a renal functional benefit in patients with Stage 3-5 chronic kidney disease (CKD). PATIENTS AND METHODS: The change in estimated glomerular filtration rate (eGFR) over time was compared between 462 patients with baseline CKD 3-5 that underwent RPN with main arterial clamping (MAC) (n = 375, 81.2%), SAC (n = 48, 10.4%) or OC (n = 39, 8.4%) using a multivariable linear mixed-effects model. All follow-up eGFRs, including baseline and follow-up between 3 and 24 months, were included in the model for analysis. The median follow-up was 12.0 months (interquartile range 6.7-16.5; range 3.0-24.0 months). RESULTS: In the multivariable linear mixed-effects model adjusting for characteristics including tumour size and the R.E.N.A.L. (Radius; Exophytic/Endophytic; Nearness; Anterior/Posterior; Location) Nephrometry Score, the change in eGFR over time was not significantly different between SAC and MAC RPN (ß = -1.20, 95% confidence interval [CI] -5.45, 3.06; P = 0.582) and OC and MAC RPN (ß = -1.57, 95% CI -5.21, 2.08; P = 0.400). Only 20 (15 MAC, two SAC, three OC) patients overall had progression of their CKD stage at last follow-up. The mean ischaemia time was 17 min for MAC and 15 min for SAC. There was no benefit to SAC or OC in terms of blood loss, perioperative complications, length of stay, or surgical margins. CONCLUSION: SAC and OC techniques during RPN were not associated with benefit in preservation of eGFR in patients with baseline CKD.

Cannabis constituents reduce seizure behavior in chemically-induced and scn1a-mutant zebrafish.

Current antiepileptic drugs (AEDs) are undesirable for many reasons including the inability to reduce seizures in certain types of epilepsy, such as Dravet syndrome (DS) where in one-third of patients does not respond to current AEDs, and severe adverse effects that are frequently experienced by patients. Epidiolex, a cannabidiol (CBD)-based drug, was recently approved for treatment of DS. While Epidiolex shows great promise in reducing seizures in patients with DS, it is used in conjunction with other AEDs and can cause liver toxicity. To investigate whether other cannabis-derived compounds could also reduce seizures, the antiepileptic effects of CBD, Δ9-tetrahydrocannabinol (THC), cannabidivarin (CBDV), cannabinol (CBN), and linalool (LN) were compared in both a chemically-induced (pentylenetetrazole, PTZ) and a DS (scn1Lab-/-) seizure models. Zebrafish (Danio rerio) that were either wild-type (Tupfel longfin) or scn1Lab-/- (DS) were exposed to CBD, THC, CBDV, CBN, or LN for 24 h from 5 to 6 days postfertilization. Following exposure, total distance traveled was measured in a ViewPoint Zebrabox to determine if these compounds reduced seizure-like activity. Cannabidiol (0.6 and 1 µM) and THC (1 and 4 µM) significantly reduced PTZ-induced total distance moved. At the highest THC concentration, the significant reduction in PTZ-induced behavior was likely the result of sedation as opposed to antiseizure activity. In the DS model, CBD (0.6 µM), THC (1 µM), CBN (0.6 and 1 µM), and LN (4 µM) significantly reduced total distance traveled. Cannabinol was the most effective at reducing total distance relative to controls. In addition to CBD, other cannabis-derived compounds showed promise in reducing seizure-like activity in zebrafish. Specifically, four of the five compounds were effective in the DS model, whereas in the PTZ model, only CBD and THC were, suggesting a divergence in the mode of action among the cannabis constituents.

Does the presence of an intact primary increase the risk of nonelective colorectal surgery in patients treated with bevacizumab?

AIM: In patients with incurable metastatic colorectal cancer (mCRC), resection of the primary tumour is debated; however, patients with intact primaries may be at a higher risk of complications requiring surgery when receiving treatment with bevacizumab. Our aim was to estimate the risk of nonelective colorectal surgery in patients undergoing bevacizumab therapy for mCRC and evaluate the association between intact primary tumours and risk of nonelective surgery. METHOD: We designed a population-based, retrospective cohort study using administrative and cancer registry data in Ontario, Canada. We included patients with mCRC who received bevacizumab from 1 January 2008 to 31 December 2014. The primary outcome was nonelective colorectal surgery after initiation of bevacizumab. We determined the cumulative incidence of nonelective colorectal surgery among patients with previously resected and unresected primaries, accounting for the competing risk of death. We explored the relationship between previous resection of the primary and need for nonelective surgery using a cause-specific hazards model, controlling for patient, tumour and treatment factors. RESULTS: We identified 1840 (32.7%) patients with intact primaries and 3784 (67.3%) patients with prior resection. The cumulative incidence of nonelective surgery 1 year after initiating bevacizumab for all patients was 3.9% (95% CI 3.4-4.5%). One-year cumulative incidence was higher in those with intact primaries than in those with resected primaries (6.1% vs 2.9%, P < 0.0001). After adjustment, an intact primary remained strongly associated with nonelective colorectal surgery (hazard ratio = 2.89, 95% CI 2.32-3.61; P < 0.0001). CONCLUSION: Bevacizumab is associated with a low but meaningful risk for serious gastrointestinal complications, necessitating vigilance, particularly among patients with an intact primary tumour.

Pasture allowance, duration, and stage of lactation-Effects on early and total lactation animal performance.

Pasture availability in early spring can be limited due to climatic effects on grass production, increasing the likelihood of feed deficits in early lactation of spring-calving pasture-based systems. We hypothesized that restricting pasture allowance (PA) when animals are at peak milk production will have more negative implications on milk production compared with restricting animals before this period. A total of 105 cows were assigned to 1 of 7 grazing treatments from March 14 to October 31, 2016 (33 wk). The control treatment was offered a PA to achieve a postgrazing sward height > 3.5 cm and mean pasture allowance of 15.5 kg of dry matter per cow. The remaining treatments were offered a PA representing 60% of that offered to the control for a duration of 2 or 6 wk from March 14 (mid-March; MMx2 and MMx6), March 28 (end of March; EMx2 and EMx6), or April 11 (mid-April; MAx2 and MAx6). Within grazing treatment, animals were also assigned to 1 of 2 calving dates (early and late) based on days in milk (DIM) on March 14. Early calved (EC) cows were ≥36 DIM, while late calved (LC) were ≤35 DIM. Restricting PA for 2 and 6 wk reduced daily milk yield (-1.6 and -2.2 kg/cow, respectively), cumulative milk protein yield (-4.0 and -6.3 kg/cow, respectively), and cumulative milk solids yield (-5.8 and -9.5 kg/cow, respectively) in the first 10 wk of the experiment. Daily milk yield was similar across the treatments at the end of the 33-wk period (16.8 kg/cow, average of all treatments), as was daily milk solids yield (1.40 kg/cow). Cows in the EC group produced less milk over the first 10 wk of the experiment (20.0 kg/cow per day) compared with the LC animals (22.1 kg/cow per day). However, body weight was greater (+15 kg/cow) in the EC animals compared with the LC, while body condition score was similar (2.85). This outcome indicates that animals that are restricted later in early lactation (circa onset of peak milk production) partition a greater proportion of available energy to maintenance, resulting in greater losses in milk production. These data indicate that despite the immediate reduction in milk production, restricting intake of grazing cows to 80% of that required to achieve spring grazing targets for postgrazing sward height for up to 6 wk may be used as a method of managing short-term pasture deficits on farm with minimal effects on total lactation performance.

Associations between colostrum management, passive immunity, calf-related hygiene practices, and rates of mortality in preweaning dairy calves.

Calves are particularly vulnerable to health issues before weaning and experience high rates of mortality. Poor colostrum quality or substandard colostrum management, combined with poor hygiene, can increase disease susceptibility, contributing to elevated mortality rates. This study aimed to assess colostrum and calf management together with subsequent mortality rates in preweaning calves. Forty-seven Irish spring-calving, pasture-based dairy herds were enrolled in the study. To investigate whether colostrum and hygiene practices change as the calving season progresses, each farm was visited in both the first and last 6 wk of the calving season. The concentration of IgG in 250 colostrum samples and 580 calf serum samples was determined by radial immunodiffusion assay. Mean colostrum IgG concentration was 85 mg/mL, and mean calf serum IgG concentration was 30.9 and 27.1 mg/mL, respectively, in the first and last 6 wk of the calving season. Smaller herd size and younger age at sampling were associated with higher calf serum IgG concentration. Dairy breed calves were associated with higher serum IgG concentrations compared with beef breed calves; no association was detected based on sex. For feeding equipment hygiene, we assessed the presence of protein residues and found that hygiene levels tended to worsen from the first to the final 6 wk of the calving season. We found no association between feeding equipment hygiene and herd size or 28-d calf mortality rate. Colostrum and calf management practices were not associated with either calf serum IgG concentration or 28-d calf mortality rate. We found that IgG concentration in colostrum produced in Irish dairy herds was generally good, although large variation existed, emphasizing the need for assessment of colostrum before feeding. Results also suggested that hygiene practices associated with calf rearing can be improved, particularly in the latter half of the calving season.

Predicting the dry matter intake of grazing dairy cows using infrared reflectance spectroscopy analysis.

The objective of this study was to compare mid-infrared reflectance spectroscopy (MIRS) analysis of milk and near-infrared reflectance spectroscopy (NIRS) analysis of feces with regard to their ability to predict the dry matter intake (DMI) of lactating grazing dairy cows. A data set comprising 1,074 records of DMI from 457 cows was available for analysis. Linear regression and partial least squares regression were used to develop the equations using the following variables: (1) milk yield (MY), fat percentage, protein percentage, body weight (BW), stage of lactation (SOL), and parity (benchmark equation); (2) MIRS wavelengths; (3) MIRS wavelengths, MY, fat percentage, protein percentage, BW, SOL, and parity; (4) NIRS wavelengths; (5) NIRS wavelengths, MY, fat percentage, protein percentage, BW, SOL, and parity; (6) MIRS and NIRS wavelengths; and (7) MIRS wavelengths, NIRS wavelengths, MY, fat percentage, protein percentage, BW, SOL, and parity. The equations were validated both within herd using animals from similar experiments and across herds using animals from independent experiments. The accuracy of equations was greater for within-herd validation compared with across-herds validation. Across-herds validation was deemed the more suitable method to assess equations for robustness and real-world application. The benchmark equation was more accurate [coefficient of determination (R2) = 0.60; root mean squared error (RMSE) = 1.68 kg] than MIRS alone (R2 = 0.30; RMSE = 2.23 kg) or NIRS alone (R2 = 0.16; RMSE = 2.43 kg). The combination of the benchmark equation with MIRS (R2 = 0.64; RMSE = 1.59 kg) resulted in slightly superior fitting statistics compared with the benchmark equation alone. The combination of the benchmark equation with NIRS (R2 = 0.58; RMSE = 1.71 kg) did not result in a more accurate prediction equation than the benchmark equation. The combination of MIRS and NIRS wavelengths resulted in superior fitting statistics compared with either method alone (R2 = 0.36; RMSE = 2.15 kg). The combination of the benchmark equation and MIRS and NIRS wavelengths resulted in the most accurate equation (R2 = 0.68; RMSE = 1.52 kg). A further analysis demonstrated that Holstein-Friesian cows could predict the DMI of Jersey × Holstein-Friesian crossbred cows using both MIRS and NIRS. Similarly, the Jersey × Holstein-Friesian animals could predict the DMI of Holstein-Friesian cows using both MIRS and NIRS. The equations developed in this study have the capacity to predict DMI of grazing dairy cows. From a practicality perspective, MIRS in combination with variables in the benchmark equation is the most suitable equation because MIRS is currently used on all milk-recorded milk samples from dairy cows.

Meta-analysis of the effect of perioperative intravenous lidocaine on return of gastrointestinal function after colorectal surgery.

BACKGROUND: Return of normal gastrointestinal (GI) function is a critical determinant of recovery after colorectal surgery. The aim of this meta-analysis was to evaluate whether perioperative intravenous (IV) lidocaine benefits return of gastrointestinal function after colorectal resection. METHODS: A comprehensive search of Ovid Medline, PubMed, Embase, Cochrane library, and clinicaltrials.org was performed on 1st July 2018. A manual search of reference lists was also performed. Inclusion criteria were as follows: randomized controlled trials (RCTs) of intravenous (IV) lidocaine administered perioperatively compared to placebo (0.9% saline infusion) as part of a multimodal perioperative analgesic regimen, human adults (> 16 years), and open or laparoscopic colorectal resectional surgery. EXCLUSION CRITERIA: non-colorectal surgery, non-placebo comparator, children, non-general anaesthetic, and pharmacokinetic studies. The primary endpoint was time to first bowel movement. Secondary endpoints were time to first passage of flatus, time to toleration of diet, nausea and vomiting, ileus, pain scores, opioid analgesia consumption, and length of stay. RESULTS: One hundred and ninety one studies were screened, with 9 RCTs meeting inclusion criteria (405 patients, four laparoscopic and five open surgery studies). IV lidocaine reduced time to first bowel movement compared to placebo [seven studies, 325 patients, mean weighted difference - 9.54 h, 95% CI 18.72-0.36, p = 0.04]. Ileus, pain scores, and length of stay were reduced with IV lidocaine compared with placebo. CONCLUSIONS: Perioperative IV lidocaine may improve recovery of gastrointestinal function after colorectal surgery. Large-scale effectiveness studies to measure effect size and evaluate optimum dose/duration are warranted.

Routine monitoring of liver function tests in lung cancer resections - a necessary burden?

BACKGROUND: Increased availability of routine investigations results in significant over-investigation, burdening patients with unnecessary tests as well as increasing cost. We aimed to identify the extent of monitoring of liver function tests in lung resections, and to ascertain whether any impact on clinical decision-making occurred. METHODS: Cases were identified using theatre records coded as "lobectomy/bilobectomy" in the three-month period 20 June 2017 to 20 September 2017. Electronic records were used to collect patient data. RESULTS: A total of 91 cases were included; 77 (85%) patients had 1 set of pre-operative LFTs, 12 (13%) patients had 2 sets, and 2 (2%) patients had 0 sets; 69 (76%) had normal LFTs pre-operatively; 298 sets of LFTs were measured post-operatively, with a median of 3 sets per patient; 61 (67%) patients had either normal or static LFTs post-operatively, 13 (14%) had isolated rise in GGT, 16 (17%) had derangement of ALT and AST, and 1 patient (1%) had deranged ALP. Altered clinical decision-making due to LFTs derangement was recorded in two cases (2%). CONCLUSION: Clinicians have an obligation to justify expense, and practise in a cost-effective manner. Our data suggest that the routine perioperative monitoring of LFTs in thoracic surgery does not give any clear benefit to patient care.