A randomized controlled trial evaluating the effect of providing a rest period during long-distance transportation of surplus dairy calves: Part II. Impact on hematological variables.

The objective of this randomized controlled trial was to determine if providing a rest stop including provision of feed and water between periods of continuous transportation mitigates the impact of long-distance transportation on markers of energy status and hydration in calves transported by road for 16 h. This study was conducted between September 2022 to January 2023 and included male and female Holstein and crossbred dairy calves ≥7 d old from 2 commercial dairy farms in Ontario, Canada (n = 96). On the day before transportation, calves were enrolled and randomly assigned to one of 2 treatment groups: 1) continuous transportation by road for 16 h or 2) 8 h of transport, 8 h of rest, and a further 8 h of transport to a single calf-raising facility. Calves that received a rest stop were fed 2 L of milk replacer at the time of unloading for the rest period and again immediately before reloading for the second leg of the journey. Blood samples were collected before and after transportation as well as daily for 3 d following arrival to the calf-raising facility. Serum was analyzed for concentrations of ß-hydroxybutyrate (BHBA), nonesterified fatty acid (NEFA), haptoglobin, and creatine kinase, while acid-base disturbances were evaluated within 1 h of collection of whole blood to assess glucose, sodium, potassium, ionized calcium, hematocrit, hemoglobin, pH, base excess, pO2, TCO2, HCO3, pCO2, and sO2. Mixed linear regression models with repeated measures were built to assess the effect of treatment group, age at transportation, breed, and sex on these parameters. Immediately after transportation, calves that received the rest period had lower BHBA (-68.04 µmol/L, 95% CI: -99.59 to -36.49), NEFA (-0.14 mmol/L, 95% CI -0.22 to -0.07), and sodium (-1.10 mmol/L, 95% CI = -2.18 to -0.02), and higher glucose (0.48 mmol/L, 95% CI = 0.21 to 0.74), potassium (0.27 mmol/L, 95% CI = 0.11 to 0.43), ionized calcium (0.06 mmol/L, 95% CI = 0.03 to 0.08), and sO2 (8.76%, 95% CI = 1.61 to 15.91) compared with calves that were continuously transported for 16 h. Additionally, calves transported between 11 and 12 d old had lower hematocrit (-1.22%, 95% CI = -2.19 to -0.25), hemoglobin (-3.07 g/L, 95% CI = -5.70 to -0.43), haptoglobin (-0.13 g/L, 95% CI = -0.23 to -0.02), and potassium (-0.13 mmol/L, 95% CI = -0.22 to -0.04) and higher sodium (0.83 mmol/L, 95% CI = 0.03 to 1.63) than 7-8 d old calves. Furthermore, calves that were 13-24 d old at transport had lower haptoglobin (-0.16 g/L, 95% CI = -0.27 to -0.06) and potassium (-0.14 mmol/L, 95% CI = -0.23 to -0.05), and higher sodium (1.02 mmol/L, 95% CI = 0.22 to 1.82) and ionized calcium (0.02 mmol/L, 95% CI = 0.002 to 0.035) compared with calves transported at 7-8 d old. The results of this trial demonstrate that a rest period improves energy status upon arrival to a calf-raising facility, suggesting that the benefit of a rest period may be mostly related to the provision of mid-journey milk meals.

A randomized controlled trial evaluating the effect of providing a rest period during long-distance transportation of surplus dairy calves: Part I. Impact on health, growth, and activity.

The objective of this randomized controlled trial was to determine if providing a rest period (RP) to surplus calves transported for 16 h reduced the impact of long-distance transportation on health, growth, and activity after arrival to a calf-raising facility. Between September 2022 to January 2023, 6 to 24 d old surplus calves were randomly assigned to one of 2 treatment groups: 1) continuous transportation by road for 16 h (n = 86) or 2) 8 h of transport, 8 h RP, then a further 8 h of transport to a single commercial calf-raising facility in Ontario, Canada (n = 84). Calves that received the RP were fed 2 L of milk replacer at the time of unloading for the RP and again before reloading for the second leg of transportation. Calves were weighed before and after transportation and once weekly until they left the calf-raising facility at 11 weeks after arrival. Additionally, fecal consistency and respiratory health were assessed immediately before and after transportation, as well as twice daily following arrival. The odds of abnormal fecal and respiratory scores were assessed with mixed effects logistic regression models, whereas cox proportional hazards models were used to evaluate the hazard of treatment for diarrhea and respiratory disease. To evaluate weight loss during transportation, average daily gain, lying bouts, and steps, mixed linear regression models were used. Furthermore, mixed logistic regression models with repeated measures were built to assess associations with the odds of having a sunken flank and prolonged skin tent. There were no statistical differences in the odds of abnormal fecal or respiratory scores or the treatment for diarrhea between treatment groups; however, there was evidence that calves that received a rest period had a higher hazard of treatment for respiratory disease. Calves >10 d old had reduced odds of having an abnormal respiratory score and calves 13-24 d old had lower odds of arriving with a prolonged skin tent, lower odds of abnormal fecal score, and reduced hazard of treatment for diarrhea compared with calves 6-8 d old at transportation. During transportation, calves that received a rest period lost less weight than continuously transported calves. With respect to ADG over the 77-d study, an interaction between age at transport and treatment group was identified where calves aged 9 to 10 d old and received a rest period had higher ADG compared with calves that were 9 to 10 d old and did not receive a rest period. As for calf activity, calves receiving an RP spent more time lying on the day after transportation compared with calves that were continuously transported. The results of this trial show few differences in the health and growth of calves having a RP compared with those that underwent continuous transport. Furthermore, calves receiving a rest period may arrive more fatigued than calves who arrive to their destination in a shorter period of time overall. Transporting calves at older ages presents an opportunity to reduce the impact of long-distance transportation on subsequent health, growth, and activity.

Effects of transportation duration on lying behavior in young surplus dairy calves.

Surplus dairy calves are commonly transported long distances from dairy farms to calf-raising facilities and livestock auctions. Current calf transportation research mainly describes physiological changes resulting from transportation. However, few studies have described the effects of transportation on calf behavior. The main objective of this study was to determine the effects of different durations of transportation (6, 12, and 16 h) on lying time and bouts in surplus dairy calves. A secondary objective of this study was to investigate whether calf age affected lying behavior around transportation. Surplus dairy calves (n = 175) were transported in 7 cohorts from 5 commercial dairy farms in Ontario to a single veal facility. On the day of transportation (d 0), calves were randomly assigned to 1 of 3 treatment groups: (1) 6 h (n = 60), (2) 12 h (n = 58), or (3) 16 h (n = 57) of continuous transportation by road. Calf lying and standing behaviors were recorded using HOBO data loggers (Hobo Pendant G Acceleration Data Logger, Onset Computer Corporation). Daily lying time (h/d) and bouts (no./d) were assessed from -1 to 3 d relative to transportation. The total time spent lying during transportation was assessed as the percentage of time lying (min lying/total min on the trailer × 100) from the time each calf was loaded onto the trailer until the time each calf was unloaded at the veal facility (n = 167). On the day of transportation (d 0), calves transported for 12 and 16 h spent less time lying (6 h: 17.1 h/d; 12 h: 15.9 h/d; 16 h: 15.0 h/d) and had more lying bouts (6 h: 21.9 bouts/d; 12 h: 25.8 bouts/d; 16 h: 29.8 bouts/d) compared with those transported for 6 h. On the day after transportation (d 1), calves transported for 16 h spent more time lying down than calves transported for 6 h (19.9 h/d vs. 18.8 h/d, respectively). In addition, during transportation, calves transported for 12 h and 16 h spent 5.8% and 7.6% more time lying down, respectively, than calves transported for 6 h. On each day relative to transportation (d -1 to 3), younger calves (2 to 5 d of age) spent a greater amount of time lying down than older calves (6 to 19 d of age) and, overall, had a greater number of lying bouts. The results of this study suggest that longer durations of transportation influence the lying behavior of surplus dairy calves, resulting in more fatigue during and after the journey and, therefore, potentially have negative implications for calf welfare. Additionally, longer durations of transportation may have greater influence on younger calves than older calves.

A randomized controlled trial investigating the effect of transport duration and age at transport on surplus dairy calves: Part I. Impact on health and growth.

Calves arriving to veal and dairy-beef facilities in poor condition are at risk of future health challenges and reduced growth rates, and limited knowledge is available on how time in transit affects subsequent health and growth of these animals. The objective of this randomized controlled trial was to understand the effects of transport duration on diarrhea, respiratory disease, and growth of surplus calves destined for veal production following 6, 12, or 16 h of continuous road transport. Surplus dairy calves (n = 175; 7 transport cohorts) from 5 commercial dairy farms in Ontario, Canada, were enrolled on the day of birth. These calves were clinically examined daily on the source farms until the day before transport and on a daily basis for the first 14 d at the veal farm. On the day of transport, they were randomly assigned to 6, 12, or 16 h of transport to a veal farm. A blood sample was collected between 24 and 48 h of birth to assess transfer of passive immunity status. Calves were weighed at birth, before and immediately after transport, as well as 24, 48, and 72 h after unloading. Calves were also weighed 14 and 50 d after transport. Health exams were conducted daily at the source farm, immediately before and after transport, and once daily for 14 d thereafter to evaluate clinical signs of diarrhea, respiratory disease, dehydration, and navel inflammation. Mixed effects Poisson regression models were used to evaluate variables associated with the number of days with abnormal respiratory and fecal scores, whereas mixed logistic regression models with repeated measures were built to assess the probability of a calf having abnormal respiratory scores, abnormal fecal scores, or dehydration by day after arrival to the facility. A mixed model with repeated measures was used to evaluate calf weight at each time point at which body weight was measured after transport, whereas a mixed linear regression model was used to evaluate factors associated with average daily gain (ADG) in the 50 d after transport. Calves transported for 16 h had greater incidence of abnormal fecal scores compared with 6 h in the 14 d after transport. In addition, an interaction between age and duration of transport on the number of days with abnormal respiratory scores was identified, where calves older than 7 d of age had reduced incidence of abnormal respiratory score compared with calves 2 to 6 d old, even when transported for 16 h. As for growth, age at transport was positively associated with ADG in the 50 d of observation; however, no differences were observed between transport duration groups. These findings highlight that transporting calves for a longer duration negatively affects subsequent health, and calves greater than 1 wk of age experience improved health and growth after transport compared with their younger counterparts.

A randomized controlled trial investigating the effect of transport duration and age at transport on surplus dairy calves: Part II. Impact on hematological variables.

Surplus dairy calves often arrive at veal and dairy-beef rearing facilities with health and blood metabolite level abnormalities, which can affect their welfare and performance, predisposing them to future health challenges. The objective of this randomized controlled trial was to investigate the effects of transport duration and age at the time of transport on blood parameters in surplus dairy calves following 6, 12, or 16 h of continuous road transportation. All surplus calves from 5 commercial dairy farms in Ontario were enrolled and examined daily before transport (n = 175). On the day of transportation, calves were weighed, blood sampled, and randomly assigned to 6, 12, or 16 h of transportation. Blood samples were then collected immediately after transportation, as well as 24, 48, and 72 h thereafter. Serum was analyzed at a provincial diagnostic laboratory for nonesterified fatty acids (NEFA), ß-hydroxybutyric acid (BHBA), creatine kinase (CK), cholesterol, and haptoglobin. In addition, blood gas and electrolyte values were also assessed at the time of sample collection. Mixed models with repeated measures were used to assess the effects of transport duration, breed, sex, transfer of passive immunity status, weight before transportation, and age at transportation on blood parameters. Immediately following transportation, NEFA and BHBA were greater for calves transported for 12 h (Δ = 0.22 mmol/L NEFA, 95% CI = 0.15 to 0.30; Δ = 0.04 mmol/L BHBA, 95% CI = 0.02 to 0.06) and 16 h (Δ = 0.35 mmol/L NEFA, 95% CI = 0.27 to 0.42; Δ = 0.10 mmol/L BHBA, 95% CI = 0.08 to 0.11) compared with calves transported for 6 h. Glucose was lower immediately following transportation in calves transported for 16 h compared with 6 h (Δ = -15.54 mg/dL, 95% CI = -21.54 to -9.54). In addition, pH and HCO3- were lower in calves transported for 12 (Δ = -0.09 pH, 95% CI = -0.13 to -0.05; Δ = -1.59 mmol/L HCO3-, 95% CI = -2.61 to -0.56) and 16 h (Δ = -0.07 pH, 95% CI = -0.12 to -0.03; Δ = -1.95 mmol/L HCO3-, 95% CI = -2.95 to -0.95) compared with calves transported for 6 h. Calves transported between 15 and 19 d of age had a higher concentration of cholesterol and CK (Δ = 0.27 mmol/L cholesterol; 37.18 U/L CK) compared with 2- to 6-d-old calves, and calves 12 to 14 d old had greater reduction in HCO3- (Δ = -0.92 mmol/L) compared with 2- to 6-d-old calves. These findings show that transporting calves for long distances results in lower glucose concentration and suboptimal energy status, and that this effect varies based on the calf's age.

Characterizing the literature surrounding transportation of young dairy calves: A scoping review.

Transportation is a stressful event for cattle, as it may involve various handling practices, commingling, deprivation of food and water, and fluctuating temperatures. Calves are particularly susceptible to these stressors because their physiological and immune systems are still developing. There has been no formal synthesis of the scientific literature evaluating the effect of transportation on young dairy calf health and performance; the aim of this scoping review is to describe and characterize this body of work. We targeted both descriptive and analytic studies examining transport of calves, including listing how the effect of transport has been evaluated. Eight databases were searched for relevant articles with eligible studies being primary research articles investigating transportation of calves of either sex who were younger than 60 d of age or weighed less than 100 kg. Two reviewers independently screened the title and abstracts of 6,859 articles with 361 potentially relevant articles screened at full text. Of these, 46 were relevant and had data extracted. Articles reporting study location were conducted in the United States (n = 5), Australia (n = 3), Japan (n = 3), and New Zealand (n = 3). Common transport-related variables evaluated included time in transit (n = 13), distance of transportation (n = 8), vehicle-related factors (n = 8), and age at time of transportation (n = 4). Outcome measures varied greatly, including blood parameters (n = 28), health assessments (n = 20), weight (n = 17), behavioral metrics (n = 14), mortality (n = 7), feed intake following transportation (n = 4), salivary cortisol concentrations (n = 3), morbidity (n = 3), and isolation of Salmonella Dublin in fecal samples (n = 2). Outcome parameters were measured during transport or ranged from immediately after to one year following transportation. As the transport-related risk factors and outcomes measured assessed varied widely between studies, future quantitative synthesis (e.g., meta-analysis) in this area may be limited. Several knowledge gaps were identified, including methods to prepare calves for transportation, such as improving nutrition, administering medication, or transporting calves at an older age or weight. Further research could also focus on consistent and clear reporting of key items related to study conduct and analysis, as well as the development of a core outcome set for calf transport studies.

Identification of biomarkers measured upon arrival associated with morbidity, mortality, and average daily gain in grain-fed veal calves.

There is a strong need for management strategies that help reduce the incidence of disease and subsequent antimicrobial use in the veal industry. Biomarkers could serve as useful tools that allow producers to take preventative measures before clinical problems occur. The objective of this prospective cohort study was to identify biomarkers measured upon arrival associated with morbidity, mortality, and average daily gain (ADG) in grain-fed veal calves. Upon arrival at a grain-fed veal facility in Ontario, Canada, calves were weighed and health-scored using a standardized health-scoring system. Several metabolites were measured including creatine kinase (CK), cholesterol, haptoglobin, manganese, serum total protein, iron, cobalt, zinc, selenium, molybdenum, and IgG. Farm personnel treated calves according to their farm protocol and weighed them at 78 d after arrival. Performance, treatment, and mortality records from the facility were used for analysis. Multivariable Cox proportional hazard models were created to evaluate metabolic biomarkers associated with morbidity and mortality. A mixed linear regression model was created to determine biomarkers associated with ADG. A total of 992 male dairy calves were evaluated at arrival from January to December 2017. Of the calves evaluated, 74 calves (7.5%) died and 877 (88.4%) were treated for illness over the 11-wk period under observation. Higher levels of haptoglobin and molybdenum were associated with a greater hazard of morbidity, whereas higher weight upon arrival and higher levels of both CK and IgG were associated with a reduced hazard of morbidity. For mortality, higher weight upon arrival and higher levels of cholesterol and IgG were associated with a lower hazard of mortality occurring over the 78-d period of observation. Higher weight, cholesterol, copper, CK, iron, and IgG were associated with increased ADG, whereas increased zinc and haptoglobin were negatively associated with ADG. These results demonstrate that certain biomarkers could be used to identify high-risk calves when measured upon arrival at a veal facility. Future research should focus on determining the utility of these biomarkers to selectively target intervention strategies to improve ADG and reduce morbidity and mortality.

A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14-179.

BACKGROUND: Five-year overall survival (OS) for patients with unresectable stage III non-small cell lung cancer (NSCLC) is poor. Until recently, a standard of care was concurrent chemoradiation alone. Patients with metastatic NSCLC treated with anti-programmed death 1 antibodies have demonstrated improved OS. This trial evaluated pembrolizumab as consolidation therapy after concurrent chemoradiation in patients with unresectable stage III disease. METHODS: Patients with unresectable stage III NSCLC received concurrent chemoradiation with cisplatin and etoposide, cisplatin and pemetrexed, or carboplatin and paclitaxel and 59.4 to 66.6 Gy of radiation. Patients with nonprogression of disease were enrolled and received pembrolizumab (200 mg intravenously every 3 weeks for up to 12 months). The primary endpoint was the time to metastatic disease or death (TMDD). Secondary endpoints included progression-free survival (PFS) and OS. RESULTS: The median follow-up for 93 patients (92 for efficacy) was 32.2 months (range, 1.2-46.6 months). The median TMDD was 30.7 months (95% confidence interval [CI], 18.7 months to not reached), which was significantly longer than the historical control of 12 months (P < .0001). The median PFS was 18.7 months (95% CI, 12.4-33.8 months), and the median OS was 35.8 months (95% CI, 24.2 months to not reached). The 1-, 2-, and 3-year OS estimates were 81.2%, 62.0%, and 48.5%, respectively. Forty patients (43.5%) completed 12 months of treatment (median number of cycles, 13.5). Symptomatic pneumonitis (grade 2 or higher) was noted in 16 patients (17.2%); these cases included 4 grade 3 events (4.3%), 1 grade 4 event (1.1%), and 1 grade 5 event (1.1%). CONCLUSIONS: Consolidation pembrolizumab after concurrent chemoradiation improves TMDD, PFS, and OS in comparison with historical controls of chemoradiation alone. Rates of grade 3 to 5 pneumonitis were similar to those reported with chemoradiation alone.

Optimized cartilage visualization using 7-T sodium ((23)Na) imaging after patella dislocation.

PURPOSE: Retropatellar cartilage lesions often occur in the course of recurrent patella dislocation. Aim of this study was to develop a more detailed method for examining cartilage tissue, in order to reduce patient discomfort and time of care. METHODS: For detailed diagnosing, a 7-T MRI of the knee joint and patella was performed in nine patients, with mean age of 26.4 years, after patella dislocation to measure the cartilage content in three different regions of interest of the patella. Axial sodium ((23)Na) images were derived from an optimized 3D GRE sequence on a 7-T MR scanner. Morphological cartilage grading was performed, and sodium signal-to-noise ratio (SNR) values were calculated. Mean global sodium values and SNR were compared between patients and volunteers. RESULTS: Two out of nine patients showed a maximum cartilage defect of International Cartilage Repair Society (ICRS) grade 3, three of grade 2, three of  grade 1, and one patient showed no cartilage defect. The mean SNR in sodium images for cartilage was 13.4 ± 2.5 in patients and 14.6 ± 3.7 in volunteers (n.s.). A significant negative correlation between age and global sodium SNR for cartilage was found in the medial facet (R = -0.512; R (2) = 0.26; p = 0.030). Mixed-model ANOVA yielded a marked decrease of the sodium SNR, with increasing grade of cartilage lesions (p < 0.001). CONCLUSIONS: Utilization of the (23)Na MR imaging will make earlier detection of alterations to the patella cartilage after dislocation possible and will help prevent subsequent disease due to start adequate therapy earlier in the rehabilitation process. LEVEL OF EVIDENCE: II.

Hepatoid adenocarcinoma of the lung: report of five cases and review of the literature.

The current diagnostic criteria for hepatoid adenocarcinoma of lung include typical acinar or papillary adenocarcinoma and a component resembling hepatocellular carcinoma and expressing α-fetoprotein (AFP). Distinguishing hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung is difficult in patients with both lung and liver masses and in patients at risk for lung and liver cancer because of smoking and viral hepatitis, respectively. We studied morphologic features of hepatoid adenocarcinoma of lung and established an immunohistochemical panel to facilitate distinction of hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung. Five cases of hepatoid adenocarcinoma of lung were stained with hematoxylin and eosin and mucicarmine for histomorphologic evaluation. The 14-marker immunohistochemical profile was established for hepatoid adenocarcinoma of lung and compared with that of hepatocellular carcinoma. Two cases of hepatoid adenocarcinoma of lung had signet-ring cell components. Three cases were pure hepatoid adenocarcinoma without components of acinar or papillary adenocarcinoma, signet-ring cells or neuroendocrine carcinoma. Like hepatocellular carcinoma, hepatoid adenocarcinoma of lung expresses CK8 (5/5), CK18 (5/5), AFP (3/5) and HepPar1 (5/5), shows cytoplasmic staining with TTF-1 (5/5) and does not express CK14 (0/5). Unlike hepatocellular carcinoma, it expresses CK5/6 (1/5), CK7 (3/5), CK19 (4/5), CK20 (1/5), HEA125 (5/5), MOC31 (5/5), monoclonal CEA (3/5) and napsin A (1/5). An immunohistochemical panel that includes a variety of cytokeratins, monoclonal CEA and EpCAM markers (HEA125 and MOC31) facilitates distinction of hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung, especially when correlated with clinical and radiologic findings. We propose modification of the current diagnostic criteria for hepatoid adenocarcinoma of lung. Tumor composition can be either pure hepatoid adenocarcinoma or hepatoid adenocarcinoma with components of typical acinar or papillary adenocarcinoma, signet-ring cells or neuroendocrine carcinoma. AFP expression is not requisite for diagnosis as long as other markers of hepatic differentiation are expressed.

In vivo evaluation of biomechanical properties in the patellofemoral joint after matrix-associated autologous chondrocyte transplantation by means of quantitative T2 MRI.

PURPOSE: To determine in vivo biomechanical properties of articular cartilage and cartilage repair tissue of the patella, using biochemical MRI by means of quantitative T2 mapping. METHODS: Twenty MR scans were achieved at 3T MRI, using a new 8-channel multi-function coil allowing controlled bending of the knee. Multi-echo spin-echo T2 mapping was prepared in healthy volunteers and in age- and sex-matched patients after matrix-associated autologous chondrocyte transplantation (MACT) of the patella. MRI was performed at 0° and 45° of flexion of the knee after 0 min and after 1 h. A semi-automatic region-of-interest analysis was performed for the whole patella cartilage. To allow stratification with regard to the anatomical (collagen) structure, further subregional analysis was carried out (deep-middle-superficial cartilage layer). Statistical analysis of variance was performed. RESULTS: During 0° flexion (decompression), full-thickness T2 values showed no significant difference between volunteers (43 ms) and patients (41 ms). Stratification was more pronounced for healthy cartilage compared to cartilage repair tissue. During 45° flexion (compression), full-thickness T2 values within volunteers were significantly increased (54 ms) compared to patients (44 ms) (p < 0.001). Again, stratification was more pronounced in volunteers compared to patients. The volunteer group showed no significant increase in T2 values measured in straight position and in bended position. There was no significant difference between the 0- and the 60-min MRI examination. T2 values in the patient group increased between the 0- and the 60-min examination. However, the increase was only significant in the superior cartilage layer of the straight position (p = 0.021). CONCLUSION: During compression (at 45° flexion), healthy patellar cartilage showed a significant increase in T2-values, indicating adaptations of water content and collagen fibril orientation to mechanical load. This could not be observed within the patella cartilage after cartilage repair (MACT) of the patella, most obvious due to a lack of biomechanical adjustment. LEVEL OF EVIDENCE: III.

Plinabulin plus docetaxel versus docetaxel in patients with non-small-cell lung cancer after disease progression on platinum-based regimen (DUBLIN-3): a phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial.

BACKGROUND: There is an unmet need for second-line and third-line treatments that are effective and tolerable for advanced or metastatic non-small-cell lung cancer (NSCLC) with no driver mutations. METHODS: In this phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial, we enrolled patients from 58 medical centres in Australia, China, and the USA. Eligible patients were adults with epidermal growth factor receptor (EGFR) wild-type NSCLC who had progressed after first-line platinum-based therapy. Patients were randomly assigned (1:1) using an independent stratified randomisation schedule with a block size of four to receive intravenous docetaxel 75 mg/m2 on day 1 and either plinabulin (30 mg/m2) or placebo on days 1 and 8 in 21-day cycles until progression, unacceptable toxic effects, withdrawal, or death. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Safety was analysed in all patients who had received at least one dose of study drug or placebo. This trial is registered with ClinicalTrials.gov (NCT02504489) and is now closed. FINDINGS: Between Nov 30, 2015, and Jan 6, 2021, 919 patients were screened for inclusion. 360 patients were excluded, and 559 were enrolled and randomly assigned to receive either docetaxel and plinabulin (n=278) or docetaxel and placebo (n=281). 406 (73%) of 559 patients were male, 153 (27%) were female, and 488 (87%) were Asian. Median OS was 10·5 months (95% CI 9·34-11·87) in the plinabulin group compared with 9·4 months (8·38-10·68) in the control group (stratified HR 0·82, 95% CI 0·68-0·99; p=0·0399). Mean OS was 15·08 months (13·42-16·74) in the plinabulin group compared with 12·77 months (11·45-14·10) in the placebo group using restricted mean survival time analysis (difference 2·31 months, 95% CI 0·18-4·44; p=0·0332). Treatment-emergent adverse events occurred in 273 (>99%) of 274 patients in the plinabulin group and 276 (99%) of 278 patients in the control group. Grade 3 or 4 gastrointestinal disorders occurred more frequently in the plinabulin group than in the placebo group, with the most frequent being diarrhoea (24 [9%] of 274 patients vs three [1%] of 278) and vomiting (six [2%] vs one [<1%]), as did transient grade 3 hypertension (50 [18%] vs eight [3%]). Treatment-emergent death was reported in 12 patients (4%) in the plinabulin group and ten patients (4%) in the placebo group. INTERPRETATION: Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population. FUNDING: BeyondSpring Pharmaceuticals.

Impact of different coils on biochemical T2 and T2* relaxation time mapping of articular patella cartilage.

OBJECTIVE: The purpose of our study was to assess T2 and T2* relaxation time values of patella cartilage in healthy volunteers using three different coils at 3.0 Tesla MRI and their influence on the quantitative values. METHODS: Fifteen volunteers were examined on the same 3-Tesla MR unit using three different coils: (i) a dedicated eight-channel knee phased-array coil; (ii) an eight-channel multi-purpose coil, and (iii) a one-channel 1H surface coil. T2 and T2* relaxation time measurements were prepared by a multi-echo spinecho respectively a gradient-echo sequence. A semi-automatic region-of-interest analysis was performed for patella cartilage. To allow stratification, a subregional analysis was carried out (deep-superficial cartilage layer). Statistical analysis-of-variance was performed. RESULTS: The mean quantitative T2 values showed statistically significant differences in all comparison combinations. The differences between the mean quantitative T2* values were slightly less pronounced than the T2 evaluation and only the comparison between (i) and (ii) showed a significant difference. The results of T2 and T2* values showed, independent of the used coil, higher values in the superficial zone compared to the deep zone (p < 0.05). Looking at the signal alterations, all coils showed clearly higher values (and thus more signal alterations as a sign of noise) in the deep layer. The validation of the reliability showed a high intra-class correlation coefficient and hence a very high plausibility (ICC was between 0.870 and 0.905 for T2 mapping and between 0.879 and 0.888 for T2* mapping). CONCLUSIONS: The present results demonstrate that biochemical T2 and T2* mapping is significantly dependent on the utilized coil.

Quantitative analysis of lumbar intervertebral disc abnormalities at 3.0 Tesla: value of T(2) texture features and geometric parameters.

T(2) relaxation time mapping provides information about the biochemical status of intervertebral discs. The present study aimed to determine whether texture features extracted from T(2) maps or geometric parameters are sensitive to the presence of abnormalities at the posterior aspect of lumbar intervertebral discs, i.e. bulging and herniation. Thirty-one patients (21 women and 10 men; age range 18-51 years) with low back pain were enrolled. MRI of the lumbar spine at 3.0 Tesla included morphological T(1) - and T(2) -weighted fast spin-echo sequences, and multi-echo spin-echo sequences that were used to construct T(2) maps. On morphological MRI, discs were visually graded into 'normal', 'bulging' or 'herniation'. On T(2) maps, texture analysis (based on the co-occurrence matrix and wavelet transform) and geometry analysis of the discs were performed. The three T(2) texture features and geometric parameters best-suited for distinguishing between normal discs and discs with bulging or herniation were determined using Fisher coefficients. Statistical analysis comprised ANCOVA and post hoc t-tests. Eighty-two discs were classified as 'normal', 49 as 'bulging' and 20 showed 'herniation.' The T(2) texture features Entropy and Difference Variance, and all three pre-selected geometric parameters differed significantly between normal and bulging, normal and herniated, and bulging and herniated discs (p < 0.05). These findings suggest that T(2) texture features and geometric parameters are sensitive to the presence of abnormalities at the posterior aspect of lumbar intervertebral discs, and may thus be useful as quantitative biomarkers that predict disease.

Magnetic resonance imaging of the knee at 3 and 7 tesla: a comparison using dedicated multi-channel coils and optimised 2D and 3D protocols.

OBJECTIVES: To show the feasibility and possible superiority of two 7 Tesla knee protocols ("7 T high resolution" and "7 T quick") using a new 28-channel knee coil compared to an optimised 3 T knee protocol using an 8-channel knee coil. METHODS: The study was approved by the ethics committee. Both 3 T and 7 T MRI of the knee were performed in 10 healthy volunteers (29.6 ± 7.9 years), with two 2D sequences (PD-TSE and T1-SE) and three isotropic 3D sequences (TRUFI, FLASH and PD-TSE SPACE). Quantitative contrast-to-noise ratio (CNR) and qualitative evaluations were performed by different readers, and intra- and inter-rater agreement was assessed. RESULTS: The signal-to-noise ratio (SNR) as well as the CNR values for cartilage-bone, cartilage-fluid, cartilage-menisci and menisci-fluid were, in most cases, higher at 7 T compared to 3 T, and the 7 T quick measurement was slightly superior compared to the 7 T high-resolution measurement. The results of the subjective qualitative analysis were higher for the 7 T measurements compared to the 3 T measurements. Inter- and intra-observer reliability was high (0.884-0.999). CONCLUSIONS: Through higher field strength and an optimal coil, resolution at 7 T can be increased and acquisition time can be reduced, with superior quantitative and comparable qualitative results compared to 3 T.

Obesity-related juvenile form of cartilage lesions: a new affliction in the knees of morbidly obese children and adolescents.

OBJECTIVES: Overweight and obesity are afflictions that lead to an increased risk of health problems including joint problems. The aim of the study was to assess the condition of articular cartilage in obese adolescent patients suffering from knee pain. METHODS: MRI of 24 knees of 20 morbidly obese patients, mean age 14.2 years, was performed in an open 1.0 Tesla MR system, where the cartilage, the quality and structure of the menisci, and the presence or absence of surrounding changes was examined. RESULTS: In all patients a cartilage lesion in at least one region of the knee could be detected. Retropatellar cartilage lesions have been found in 19 knees. Ten cartilage lesions grade I, and four lesions grade II have been described in the lateral compartment of the knee, whereas the medial compartment showed in eight cases a grade I, in 13 cases a grade II and in two cases a grade III cartilage lesion. Meniscal changes were assessed in most patients. CONCLUSION: Morbidly obese children and adolescents show major abnormalities in the articular cartilage of the knee. Whether obesity alone is the causal factor for the development of the pattern of these changes, remains to be seen. KEY POINTS: • Morbidly obese children and adolescents often suffer from knee pain • Prospective study showed cartilage and meniscal lesions in morbidly obese adolescents • MRI is an adequate tool for assessing cartilage lesions even in morbidly obese patients • It is unclear whether cartilage abnormalities are mainly due to mechanical overload.

Radon and lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Radon exposure is the second leading cause of lung cancer, following tobacco smoke. Radon is not only an independent risk factor; it also increases the risk of lung cancer in smokers. Numerous cohort, case-control, and experimental studies have established the carcinogenic potential of radon. The possibility of radon having a causative effect on other cancers has been explored but not yet proven. One of the postulated mechanisms of carcinogenesis is DNA damage by alpha particles mediated by the production of reactive oxygen species. The latter are also thought to constitute one of the common mechanisms underlying the synergistic effect of radon and tobacco smoke. With an estimated 21,000 lung cancer deaths attributable to radon in the United States annually, the need for radon mitigation is well acknowledged. The Environmental Protection Agency (EPA) has established an indoor limit of 4 picocuries (pCi)/L, and various methods are available for indoor radon reduction when testing shows higher levels. Radon mitigation should accompany smoking cessation measures in lung cancer prevention efforts.

Evaluation of an infrared thermography camera for measuring body temperature in dairy calves.

The objective of this diagnostic accuracy study was to validate an infrared thermography (IRT) camera and its software (FLIR One, FLIR, Global) for accuracy and precision for ocular temperature readings to serve as a proxy for rectal temperature in commercially housed calves. A total of 318 male Holstein calves were enrolled into this study from the day of arrival to a calf rearing facility until 14 d later. Researchers took an ocular temperature reading using an IRT camera, and a rectal temperature on each calf each day in the morning. The reference standard method for body temperature in the calves was rectal temperature. We assessed the data for agreement between the IRT and the reference standard using Pearson correlations by calf (accuracy), coefficients of determination (precision), and Bland-Altman plots for bias. In addition, a logistic regression model was built using the reference method as the outcome, with IRT as an explanatory variable to assess the diagnostic accuracy of IRT as an indicator of fever (rectal temperature ≥39.5°C). There was a negligible correlation between the IRT readings and rectal temperature (r = 0.22) and the coefficient of determination for IRT to predict rectal temperature was negligible (R2 = 0.05), suggesting poor precision. The average mean difference between the IRT data and rectal temperature was 0.55°C, and the differences between IRT and rectal formed a linear line around the mean difference, suggesting the Bland-Altman analyses showed proportional error and bias. The optimal probability cut-off for IRT readings for fever was at 39.5°C, and had a receiver operating characteristic area under the curve of 0.67, a sensitivity of 61%, a specificity of 71%, and 78% (3,134/4,427) of the samples were correctly labeled as either having a fever or not using IRT readings. In summary, the IRT camera and software were not validated for serving as a proxy for rectal temperature in commercially housed calves due to poor precision, and proportional error partially explained by ambient environmental conditions. We suggest that this infrared thermography system should not replace rectal temperature readings for use in commercially housed calves.