Selective treatment of clinical mastitis: Assessment of the Net Cash Impact on Dairy Farms Under Diverse Scenarios. A European Perspective.

Selective treatment of clinical mastitis (STCM) potentially reduces antimicrobial use without negative implications on cow's milk production or health. However, this approach comes with additional costs. The aim of this study was to evaluate the net cash impact (NCI) of implementing STCM compared with blanket treatment of clinical mastitis (BTCM) under different diagnostic-test turnaround times (24 h, 14 h, and 8 h) using a stochastic partial budget analysis with Monte Carlo simulation. The target population was European commercial dairy herds; therefore, the model inputs were primarily from European sources. Additionally, variables associated with dairy management programs were obtained from USDA sources, worldwide multisite clinical trials, and expert opinion. The output was calculated by subtracting the cost of STCM from the cost of BTCM and it represented the expected NCI if a herd switched from BTCM to STCM. Depending on the time-to-treatment efficiency and diagnostic-test turnaround time, the expected mean NCI, assuming that STCM has no impact on the cow's future health or production, ranged from +€8.7 to +€12.4 per case with 72.4% to 84.8% of the iterations being ≥ €0. Moreover, using the numerically favorable health and production effects of STCM reported in the literature, the expected mean NCI ranged from +€44.5 to +€48.1 per case with 93.6% to 95.4% of the iterations being ≥ €0. The variables with the greatest contribution to NCI variance were proportion of gram-positive cases (39.2% of the variance) and days out of the tank for treated cows (22.0%). However, if future cow's health and production were accounted for, culling risk (24.6%), recurrence risk (19.4%), and milk yield (10.6%) would have the greatest contribution to NCI. The sensitivity analysis indicated that farms with high clinical mastitis incidence, low proportion of gram-positive cases, large number of days out of the tank for treated cows, higher milking frequency or using automatic milking systems, not using the highest priced diagnostic tests, and having high antimicrobial treatment costs are the best candidates for STCM. Improving time-to-treatment efficiency, for example, by using a rapid diagnostic test, leads to a favorable NCI, while high daily milk yield and milk price enhances the NCI in already positive scenarios. Finally, the cash flow entirely depends on future cow's health and milk yield. In conclusion, results indicate that overall, STCM is a practice that positively impacts the NCI of many herds.

Gastrointestinal parasite community structure in horses after the introduction of selective anthelmintic treatment strategies.

A relatively new method to study the species richness and diversity of nematode parasites in grazing animals is to perform deep sequencing on composite samples containing a mixture of parasites. In this work, we compared species composition of strongyles in two groups of horses as a function of egg count and age, based on a DNA barcoding approach. Faecal egg counts and larval cultures were obtained from nearly 300 horses, i.e., domestic horses (n = 167) and trotters (n = 130) sampled nationwide. The second internal transcribed spacer region (ITS2) of strongyle nematodes in the larval cultures was first amplified using barcoded universal primers and then sequenced on the PacBio platform. Subsequently, bioinformatic sequence analysis was performed using SCATA to assign operational taxonomic units (OTU). Finally, species occurrence and composition were assessed using R. ITS2 sequences were found in the majority (89%) of larval samples. Sequencing yielded an average of 140 (26 to 503) reads per sample. The OTUs were assigned to 28 different taxa, of which all but three could be identified as species. The average relative abundance of the seven most abundant species (all Cyathostominae) accounted for 87% of the combined data set. The three species with the highest prevalence in both horse groups were Cyathostomum catinatum, Cylicocyclus nassatus and Cylicostephanus calicatus, and they were frequently found in different combinations with other species regardless of horse group. Interestingly, this result is largely consistent with a previous Swedish study based on morphological analysis of adult worms. In addition, two migratory strongylids (Strongylus vulgaris and S. edentatus) occurred in few domestic horses and trotters. Except for C. minutus and C. nassatus, which decreased with age, and C. catinatum and S. vulgaris, which increased, no specific trends were observed with respect to horse age. Taken together, these results are broadly consistent with data obtained before the introduction of selective targeted treatment in Sweden in 2007. All in all, our results suggest that this treatment strategy has not led to a significant change in strongyle nematode community structure in Swedish horses. The study also confirms that nemabiome analysis in combination with diversity index analysis is an objective method to study strongyle communities in horses.

Supplementation of minerals and vitamins influences optimal targeted selective treatment thresholds for the control of gastro-intestinal nematodes in lambs.

Targeted Selective Treatment (TST) is a gastrointestinal nematode (GIN) control strategy where anthelmintic treatment decisions are made at an individual animal level. TST has been proven to reduce anthelmintic use and subsequently slow down anthelmintic resistance development, however questions remain regarding optimal TST methods and their applicability across farms. In this study, the influence of Mineral and Vitamin (MV) supplementation on optimal energy utilisation (EU) TST thresholds was assessed on three Welsh farms. In total, 360 lambs were split into two groups, MV supplemented and control, and were treated with an anthelmintic against GIN at the midway point of the experiment. Lambs that improved their EU efficiency post treatment were deemed to have benefited from anthelmintic treatment. Optimal EU TST thresholds was determined for each treatment group per farm using Youden's J statistic where the treatment threshold retrospectively exhibiting the greatest combined sensitivity and specificity in correctly identifying lambs benefiting from treatment was deemed to be optimal. Results demonstrated that the optimal EU TST threshold was higher in MV supplemented groups at 0.72, 0.71 and 0.56 versus 0.58, 0.67, 0.51 for control groups on each respective farm. Identification of lambs for TST was more effective when using an optimised EU TST threshold, compared to when using the standard EU TST threshold of 0.66. The study highlights that applying standard EU TST thresholds may not be appropriate on all commercial farms with factors including MV status as noted in this study likely to influence optimal EU TST thresholds. Additional refinement of TST systems can further strengthen their applicability across sheep flocks.

A "Test-to-Treat" Pad for Real-Time Visual Monitoring of Bacterial Infection and On-Site Performing Smart Therapy Strategies.

Skin infections are major threats to human health, causing ∼500 incidences per 10 000 person-year. In patients with diabetes mellitus, particularly, skin infections are often accompanied by a slow healing process, amputation, and even death. Timely diagnosis of skin infection strains and on-site therapy are vital in human health and safety. Herein, a double-layered "test-to-treat" pad is developed for the visual monitoring and selective treatment of drug-sensitive (DS)/drug-resistant (DR) bacterial infections. The inner layer (using carrageenan hydrogel as a scaffold) is loaded with bacteria indicators and an acid-responsive drug (Fe-carbenicillin frameworks) for infection detection and DS bacteria inactivation. The outer layer is a mechanoluminescence material (ML, CaZnOS:Mn2+) and visible-light responsive photocatalyst (Pt@TiO2) incorporated elastic polydimethylsiloxane (PDMS). On the basis of the colorimetric sensing result (yellow for DS-bacterial infection and red for DR-bacterial infection), a suitable antibacterial strategy is guided and then performed. Two available bactericidal routes provided by double pad layers reflect the advantage. The controllable and effective killing of DR bacteria is realized by in situ generated reactive oxygen species (ROSs) from the combination of Pt@TiO2 and ML under mechanical force, avoiding physical light sources and alleviating off-target side effects of ROS in biomedical therapy. As a proof-of-concept, the "test-to-treat" pad is applied as a wearable wound dressing for sensing and selectively dealing with DS/DR bacterial infections in vitro and in vivo. This multifunctional design effectively reduces antibiotic abuse and accelerates wound healing, providing an innovative and promising Band-Aid strategy in point-of-care diagnosis and therapy.

Oxidative Stress Is a Concept, Not an Indication for Selective Antioxidant Treatment.

The steady-state redox status is physiologically important and therefore homeostatically maintained. Changes in the status result in signaling (eustress) or oxidative damage (distress). Oxidative stress (OS) is a hard-to-quantitate term that can be estimated only based on different biomarkers. Clinical application of OS, particularly for selective antioxidant treatment of people under oxidative stress, requires quantitative evaluation and is limited by the lack of universal biomarkers to describe it. Furthermore, different antioxidants have different effects on the redox state. Hence, as long as we do not have the possibility to determine and quantify OS, therapeutic interventions by the "identify-and-treat" approach cannot be assessed and are, therefore, not likely to be the basis for selective preventive measures against oxidative damage.

Invited review: Selective treatment of clinical mastitis in dairy cattle.

Treatment of clinical mastitis (CM) and use of antimicrobials for dry cow therapy are responsible for the majority of animal-defined daily doses of antimicrobial use (AMU) on dairy farms. However, advancements made in the last decade have enabled excluding nonsevere CM cases from antimicrobial treatment that have a high probability of cure without antimicrobials (no bacterial causes or gram-negative, excluding Klebsiella spp.) and cases with a low bacteriological cure rate (chronic cases). These advancements include availability of rapid diagnostic tests and improved udder health management practices, which reduced the incidence and infection pressure of contagious CM pathogens. This review informed an evidence-based protocol for selective CM treatment decisions based on a combination of rapid diagnostic test results, review of somatic cell count and CM records, and elucidated consequences in terms of udder health, AMU, and farm economics. Relatively fast identification of the causative agent is the most important factor in selective CM treatment protocols. Many reported studies did not indicate detrimental udder health consequences (e.g., reduced clinical or bacteriological cures, increased somatic cell count, increased culling rate, or increased recurrence of CM later in lactation) after initiating selective CM treatment protocols using on-farm testing. The magnitude of AMU reduction following a selective CM treatment protocol implementation depended on the causal pathogen distribution and protocol characteristics. Uptake of selective treatment of nonsevere CM cases differs across regions and is dependent on management systems and adoption of udder health programs. No economic losses or animal welfare issues are expected when adopting a selective versus blanket CM treatment protocol. Therefore, selective CM treatment of nonsevere cases can be a practical tool to aid AMU reduction on dairy farms.

Selective local postoperative radiotherapy for T3-T4 N0 laryngeal cancer.

PURPOSE: We aimed to investigate the appropriate postoperative radiotherapy dose and selective volume in T3-4 N0 laryngeal cancer patients treated with either total or partial laryngectomy. METHODS: Patients who received radiotherapy for locally advanced (T3-T4) and pathologic node-negative (N0) squamous cell laryngeal cancer were retrospectively evaluated. Radiotherapy was applied to median 60 Gy (range 54-60 Gy) as selective local radiotherapy (±stoma). The local treatment areas included postoperative bed + laryngeal area for patients with a partial laryngectomy, and the postoperative bed only for patients with total laryngectomy. RESULTS: The median follow-up time was 59 months and 52 patients were included. The 2­year, 5­year, and 8­year locoregional recurrence controls (LRC) were 95.6%. The 2­year and 5­year OS rates were 93.8% and 78.9%, respectively. The 5­year OS for age < 60 years was 95.8%, for above 60 years 56.5%. CONCLUSION: Our data suggest that local selective irradiation to the postoperative bed + stoma is enough in patients with T3-4 N0 laryngeal cancer without applying elective nodal irradiation.

Targeted selective treatment with anthelmintic for New Zealand dairy heifers.

We investigated whether measurement of live weight gain (LWG) could be used to deliver targeted selective treatment (TST) with anthelmintic that maintained target live weight (LW) while reducing anthelmintic use. Dairy heifers (n = 546) from four commercial, seasonal calving, pastoral New Zealand dairy herds in the Canterbury region of New Zealand were recruited to compare effects of TST, against suppressive treatment (ST), on LW and LWG in their first year at pasture. Animals were enrolled at weaning (December) and weighed ± anthelmintic treatment every month until May and then in August and September, pre-mating in October. All ST calves were treated every month with an oral anthelmintic at 1 mL/5 kg LW, delivering 0.2 mg abamectin, 8 mg levamisole and 4.5 mg oxfendazole/kg LW, (Control). TST calves received the same anthelmintic at the same time but only if either their individual LWG fell below a pre-specified, time altered, breed specific target for that group (Group target) or if their individual LWG fell below an individual, time altered target for that individual (Individual target). Faecal egg count (FEC) and serum IgA OD levels were recorded from a sample of calves throughout the study. Compared to ST, anthelmintic use was halved in both TST groups (P < 0.001) and there was no evidence for differences in the proportion of calves reaching target LW pre-mating (Control = 80 (95 % CI = 79.1-87.2 %), Group = 78.9 (95 % CI = 59.6-98.2%), Individual = 78.2 (95 % CI = 58.4-97.9 %), P = 0.935). Control calves were heavier pre-mating (310 (95 % CI = 290-330 kg) than Group (300 (95 % CI = 280-320 kg) or Individual (298 (95 % CI = 278-318 kg), P < 0.001). An interaction between FEC and time meant calves with FEC > 200 EPG grew more slowly in the autumn (P < 0.001), but more quickly in the winter (P < 0.001). FEC and IgA OD levels were consistent with levels of parasitism sufficient to impact LWG, but there was no evidence for differences between treatment groups. Sensitivity and specificity of LW and LWG as predictors of reaching target weight varied month-on-month but these results suggest monthly LWG and LW were poor indicators for AHC treatment. In conclusion, TST can be effective in reducing anthelmintic use and maintaining group level performance. LW and LWG sensitivity was 57-85 % and 66-93 %; specificity 38-83 % and 32-79.

Comparison of Immediate Blanket Treatment versus a Delayed Pathogen-Based Treatment Protocol for Clinical Mastitis Using an On-Farm Culture Test at a Commercial German Dairy Farm.

The objective of this study was to compare immediate intramammary antimicrobial treatment of mild and moderate cases of clinical mastitis (CM) with a selective treatment protocol based on on-farm culture results using Accumast®. The study was conducted at a 2600 cow commercial farm in Northeast Germany. Using a randomized design, mild and moderate clinical mastitis cases were assigned to either the blanket therapy (BT) or pathogen-based therapy (SELECT) group. Overall, 468 cases were used for final analyses (BT = 236; SELECT = 232). The percentage of cases assigned to the blanket and pathogen-based groups that received intramammary therapy were 100 and 69.9%, respectively. Implementation of a pathogen-based treatment protocol for mild and moderate CM cases resulted in no significant difference in post-event milk production, somatic cell count, survival to 30 d, and days spent in the hospital compared with a blanket therapy protocol. Cows in the SELECT group had reduced odds of being culled within 60 d post CM (odds ratio = 0.54; 95% CI = 0.31-0.93; p = 0.027). The use of a pathogen-based treatment protocol using an on-farm culture system has the potential to efficiently reduce antimicrobial use without negative effects on health.

Preliminary Assessment of Body Condition Score as a Possible Marker for the Targeted Selective Treatment of Dairy Sheep Against Gastrointestinal Nematodes.

PURPOSE: In the fight against anthelmintic resistance, targeted selective treatments (TSTs), where only a small percentage of a flock receives treatment, have become increasingly popular. Overall, implementation of such treatments can be based on various parameters including Body condition score (BCS). As infection with non-bloodsucking nematodes, frequently encountered on sheep farms in the central Mediterranean basin, commonly causes bodyweight reduction, the aim of this research is to evaluate the effectiveness of BCS as a parameter for the implementation of TSTs in lactating dairy sheep with subclinical gastrointestinal nematode (GIN) infections from the island of Sardinia, Italy. METHODS: Faecal samples from 1012 ewes divided into 2 groups (third and fifth month of lactation) were collected and their BCS recorded. Faecal egg counts and coprocultures were performed for the assessment of the GIN burden and identification of present species. RESULTS: An overall GIN prevalence of 85.4% with a mean eggs per gram (EPG) of faeces of 210.1 ± 347.3 was found. Teladorsagia spp. and Trichostrongylus spp. were the GIN genera most identified. Overall, animals with the lowest BCS had the highest EPG values and a negative correlation (r = - 0.163) between the EPG values and BCS of the studied animals was found, which was most significant for older sheep. CONCLUSION: This research confirmed BCSs and EPG values for GIN in sheep to be negatively correlated, particularly in older ewes. Application of TSTs for lactating sheep with a BCS < 2.25, especially to older ewes, could be beneficial in case of subclinical GIN infections, although further studies are needed to work out precise recommendation.

PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib.

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term referring to various clinical entities, which share the same pathogenetic mechanism. These conditions are caused by somatic gain-of-function mutations in PIK3CA, which encodes the 110-kD catalytic α subunit of PI3K (p110α). These PIK3CA mutations occur as post-zygotic events and lead to a gain of function of PI3K, with consequent constitutional activation of the downstream cascades (e.g., AKT/mTOR pathway), involved in cellular proliferation, survival and growth, as well as in vascular development in the embryonic stage. PIK3CA-related cancers and PROS share almost the same PIK3CA mutational profile, with about 80% of mutations occurring at three hotspots, E542, E545, and H1047. These hotspot mutations show the most potent effect on enzymatic activation of PI3K and consequent downstream biological responses. If present at the germinal level, these gain-of-function mutations would be lethal to the embryo, therefore we only see them in the mosaic state. The common clinical denominator of PROS disorders is that they are sporadic conditions, presenting with congenital or early childhood onset overgrowth with a typical mosaic distribution. However, the severity of PROS is highly variable, ranging from localized and apparently isolate overgrowth to progressive and extensive lipomatous overgrowth associated with life-threatening vascular malformations, as seen in CLOVES syndrome. Traditional therapeutic approaches, such as sclerotherapy and surgical debulking, are often not curative in PROS patients, leading to a recrudescence of the overgrowth in the treated area. Specific attention has been recently paid to molecules that are used and studied in the oncogenic setting and that are targeted on specific alterations of the pathway PI3K/AKT/mTOR. In June 2018, Venot et al. showed the effect of Alpelisib (BYL719), a specific inhibitor for the p110α subunit of PI3K, in patients with PROS disorders who had severe or life-threatening complications and were not sensitive to any other treatment. In these cases, dramatic anatomical and functional improvements occurred in all patients across many types of affected organ. Molecular testing in PROS patients is a crucial step in providing the conclusive diagnosis and then the opportunity for tailored therapy. The somatic nature of this group of diseases makes challenging to reach a molecular diagnosis, requiring deep sequencing methods that have to be performed on DNA extracted from affected tissue. Moreover, even analyzing the DNA extracted from affected tissue there is no guarantee to succeed in detection of the casual somatic mutation, since the affected tissue itself is highly heterogeneous and biopsy approaches can be burdened by incorrect sampling or inadequate tissue sample. We present an 8-year-old girl with CLOVES syndrome, born with a large cystic lymphangioma involving the left hemithorax and flank, multiple lipomas, and hypertrophy of the left foot and leg. She developed severe scoliosis. Many therapeutic approaches have been attempted, including Sildenafil treatment, scleroembolization, laser therapy, and multiple debulking surgeries, but none of these were of benefit to our patient's clinical status. She then started treatment with Rapamycin from May 2019, without significant improvement in both vascular malformation and leg hypertrophy. A high-coverage Whole Exome Sequencing analysis performed on DNA extracted from a skin sample showed a mosaic gain-of-function variant in the PIK3CA gene (p.H1047R, 11% of variant allele frequency). Once molecular confirmation of our clinical suspicion was obtained, after a multidisciplinary evaluation, we decided to discontinue Sirolimus and start targeted therapy with Alpelisib (50 mg/day). We noticed a decrease in fibroadipose overgrowth at the dorsal level, an improvement in in posture and excellent tolerability. The treatment is still ongoing.

Efficacy of a Novel Bi-Steric mTORC1 Inhibitor in Models of B-Cell Acute Lymphoblastic Leukemia.

The mechanistic target of rapamycin (mTOR) is a kinase whose activity is elevated in hematological malignancies. mTOR-complex-1 (mTORC1) phosphorylates numerous substrates to promote cell proliferation and survival. Eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) are mTORC1 substrates with an integral role in oncogenic protein translation. Current pharmacological approaches to inhibit mTORC1 activity and 4E-BP phosphorylation have drawbacks. Recently we described a series of bi-steric compounds that are potent and selective inhibitors of mTORC1, inhibiting 4E-BP phosphorylation at lower concentrations than mTOR kinase inhibitors (TOR-KIs). Here we report the activity of the mTORC1-selective bi-steric inhibitor, RMC-4627, in BCR-ABL-driven models of B-cell acute lymphoblastic leukemia (B-ALL). RMC-4627 exhibited potent and selective inhibition of 4E-BP1 phosphorylation in B-ALL cell lines without inhibiting mTOR-complex-2 (mTORC2) activity. RMC-4627 suppressed cell cycle progression, reduced survival, and enhanced dasatinib cytotoxicity. Compared to a TOR-KI compound, RMC-4627 was more potent, and its effects on cell viability were sustained after washout in vitro. Notably, a once-weekly, well tolerated dose reduced leukemic burden in a B-ALL xenograft model and enhanced the activity of dasatinib. These preclinical studies suggest that intermittent dosing of a bi-steric mTORC1-selective inhibitor has therapeutic potential as a component of leukemia regimens, and further study is warranted.

Bayesian estimation of diagnostic accuracy of somatic cell counts history and on-farm milk culture using Petrifilm® to identify quarters or cows that should be treated with antimicrobials in selective treatment protocols at dry off.

Bayesian latent class models were used to estimate the test accuracy (sensitivity (Se), specificity (Sp), and predictive values (NPV and PPV)) of cow-level somatic cell counts (SCC) data, quarter-level Petrifilm® on-farm milk culture, and quarter-level standard milk bacteriology for the identification of quarters that should possibly be treated with antimicrobials at dry off in dairy cows. Data of 282 cows from 9 dairy herds in Québec, Canada, with bulk tank SCC < 250,000 cells/mL were used. Estimated median herd-prevalence of infections that should be treated was 16.2 % (95 % credibility interval (CI): 11.0-22.7). Se and Sp estimates for quarter-milk culture using Petrifilm® were 82.2 % (95 %CI: 74.0-89.5) and 62.0 % (95 %CI: 58.6-65.6), respectively. Se and Sp for quarter-milk standard bacteriology were 67.4 % (95 %CI: 55.8-81.2) and 79.6 % (95 %CI: 76.4-83.0), respectively. Se and Sp of different SCC scenarios and thresholds were estimated. For first parity cows, using only the last Dairy Herd Improvement (DHI) test SCC with a threshold of 100,000 cells/mL appeared quite accurate, with Se, Sp, PPV, NPV and reduction of antimicrobial usage of 85.6 % (95 %CI: 69.6-95.6), 86.0 % (95 %CI: 80.0-91.7), 58.0 % (95 %CI: 42.3-74.2), 96.4 % (95 %CI: 91.3-99.0), and 75.3 % (95 %CI: 70.7-79.3), respectively. For cows of ≥ 2nd parity, using only the last DHI test SCC with a threshold of 200,000 cells/mL resulted in Se, Sp, PPV, NPV and reduction of antimicrobial usage of 75.3 % (95 %CI: 55.8-87.3), 84.0 % (95 %CI: 78.8-89.3), 47.2 % (95 %CI: 32.0-63.7), 94.7 % (95 %CI: 89.0-97.6), and of 77.0 % (95 %CI: 73.3-80.3), respectively. Adding quarter-level milk culture using Petrifilm® to cows identified as unhealthy using cow-level SCC data improved the test accuracy (mainly the PPV) and further reduced the use of antimicrobials. For instance, in ≥ 2nd parity cows, using only the last DHI SCC with a threshold of 200,000 cells/mL, adding a subsequent Petrifilm® test increased the reduction from 77.0 % (95 %CI: 73.3-80.3) to 89.5 % (95 %CI: 86.7-91.8). Considering the availability of SCC data, the easiness of using just the last DHI test, and the high NPV that could be achieved, producers may consider using just the last DHI test as a potential tool to identify cows that should be treated with antimicrobials at dry off. It may be used alone or in combination with quarter-level on-farm Petrifilm® milk culture on high SCC cows to further reduce the use of antimicrobials by identifying quarters that need to be treated.

Gastrointestinal nematode control practices in ewes: Identification of factors associated with application of control methods known to influence anthelmintic resistance development.

Gastrointestinal nematodes (GIN) negatively impact productivity and welfare in sheep globally and are estimated to cost the European sheep industry €157-477 million annually. GIN are mainly controlled by anthelmintic treatment, however, as anthelmintic resistance becomes prominent, the routine treatment of ewes against GIN has been questioned. A questionnaire survey of 383 sheep farmers in Great Britain was conducted to identify strategies currently used to control GIN infections in ewes. Ordinal and binary regression analysis were used to identify factors associated with use of practices known to influence anthelmintic resistance development, including number and timing of ewe GIN anthelmintic treatment, targeted selective treatment (TST) of ewes, drench and move of ewes and long-acting moxidectin treatment of periparturient ewes. Participating farmers treated their ewes against GIN 1.68 times per year on average, with 42.3% and 32.1% of participating farmers worming their ewes once or twice a year on average, respectively. 17.2% of participating farmers wormed their ewes more than twice a year, and 8.4% never worm their ewes. Participating farmers who devised GIN control strategies based on SCOPS guidelines treated their ewes significantly less per year (P < 0.001), whilst those determining treatment timing based on ewe DAG scores or the time of year treated their ewes significantly more frequently (P < 0.001). Farmers who devised GIN control strategies in conjunction with their vet had greater odds of using TST (P < 0.001), as well as farmers who determined flock treatment timing based on ewe condition (P = 0.027). The use of narrow spectrum flukicides was significantly associated with reduced number of annual ewe GIN anthelmintic treatments (P < 0.001), TST of ewes against GIN (P < 0.001) and the avoidance of moving ewes to clean pastures following GIN treatment (P < 0.001). The presence of sheep scab on a farm or in the area was significantly associated with increased annual GIN treatments for ewes (P = 0.002), not using TST strategies to control GIN in ewes (P < 0.001) and moving ewes to clean pasture after anthelmintic treatment, whilst using macrocyclic lactones treatments to prevent sheep scab was significantly associated with the treatment of periparturient ewes with long-acting moxidectin (P = 0.001). This research suggests that by encouraging the application of evidence based targeted or targeted selective treatment strategies, further interaction between farmers and veterinarians/SCOPS guidance, and the uptake of best practices for controlling liver fluke and sheep scab on farms, sustainable GIN control strategies can become the common practice in ewes.

Gastrointestinal Parasitism in Miranda Donkeys: Epidemiology and Selective Control of Strongyles Infection in the Northeast of Portugal.

In Portugal, equine parasitism in pasture animals is characterized by high parasitic burden and high helminthic biodiversity; both factors are potentially pathogenic for their hosts. The decrease in the number of donkeys over the last years in Portugal, their importance in rural lowland and mountain ecosystems and pastures and the scarce information regarding their parasitism led to this research, which aimed to evaluate the parasitological status of a Miranda donkey breed population, a native breed mainly located in the northeast of Portugal. This study provides better knowledge of their gastrointestinal parasitism, particularly strongyles, and the assessment of a targeted selective treatment (TST) as an alternative control approach of their parasitism. A longitudinal observational study was developed during a period of five years in a population of 62 Miranda donkeys. At first, strategic deworming of these animals was performed every semester, but this was progressively replaced by a TST approach according to the levels of Eggs per Gram (EPG). This new deworming strategy was conducted in association with a regular parasitological monitoring of the animals every three months, being dewormed with ivermectin when egg shedding was higher than 500 EPG. Over the study period, a decrease of the annual prevalence rate of infection by gastrointestinal strongyles was observed, from 35.5% to 19.4%, as well as a negative binomial distribution of parasitic strongyles in donkeys submitted to selective anthelminthic control. The prevalence rate of infection was higher in females (39.5%), in individuals under four years (46.7%) and in those presenting a lower body condition (40.8%). The egg output was higher in animals younger than four years (589.3 EPG) than in those older than 10 years (533.6 EPG) (p < 0.05). However, no differences were observed according to sex during the study period. Results from this study allowed to note the influence of swampy pastures and of the weather changes in the epidemiology of strongylosis in Miranda donkeys. Moreover, it was possible to establish the annual epidemiological curve of strongyle egg shedding, with June being the month with the highest EPG, December having the lowest EPG and March and September showing intermediate numbers. Overall, a lower biodiversity of gastrointestinal parasites was observed. Cyathostomum sensu lato was the most prevalent genus and Strongylus vulgaris was the most observed large strongyle of the Strongylidae family. Trichostrongylus axei and Parascaris sp. were other nematodes with a minor frequency. The higher prevalence of strongyles at the beginning of the study showed a progressive decrease throughout the research period, and also for parasite biodiversity. Therefore, a targeted selective treatment seems to be a rational anthelminthic control approach in Miranda donkey strongyle infection and in other gastrointestinal parasites, since it reduces the antiparasitic treatments, the parasite' prevalence and the EPG level. However, a loss of parasite biodiversity was noted at the end of the study period, as Cyathostominae were the only isolated strongyles. This can be a challenging situation in the long run, taking the ability of these nematodes to adapt easily to any deworming program, meaning that fecal EPG monitoring should be kept as a rule to a rational parasite control program.

Conjunctival mucous membrane colour as an indicator for the targeted selective treatment of haemonchosis and of the general health status of peri-urban smallholder goats in southern Malawi.

The world's growing population is becoming increasingly centred around large cities, affording opportunities for peri-urban food production. Goats are well-suited to conversion of resources that are available in peri-urban settings into meat and occasionally milk. Haemonchus contortus has been described as "the nemesis of small ruminant production systems in tropical and subtropical regions"; hence control of haemonchosis through planned animal health management affords a pragmatic first step in improving the production efficiency of peri-urban goats. This study of peri-urban goat production investigated the potential value of targeted selective treatment of haemonchosis. 452 peri-urban goat keepers in southern Malawi were visited during three seasonal periods with relevance to the epidemiology of haemonchosis. 622, 599 and 455 individually identified goats were clinically examined during the dry season, the rainy season, and shortly after the end of the rainy season, respectively. Data were recorded for sex, age, weight, conjunctival mucous membrane colour score (FAMACHA©), body condition score (BCS) and faecal worm egg count (FEC); and where possible for pregnancy and lactation status. Animals with pale ocular mucous membranes were treated with 10 mg/kg albendazole, then re-examined 14 days later. Animals with pink mucous membranes, but FECs ≥250 eggs per gram were also re-examined and treated 14 days later. The results show high variability in growth rates deduced from the ages and bodyweights of each of 999 goats at the time of their enrolment. FAMACHA© scores alone were a poor index for the targeted selective treatment of haemonchosis, because they failed to identify too many animals that would have required treatment at different times of year and using different FAMACHA© and FEC cut-offs. Combining the indices of FAMACHA© scores ≥4, body condition scores ≥2, and age >18 months was more reliable in identifying those animals requiring treatment when different epidemiologically-relevant FEC thresholds for different seasons were taken into account. Inclusion of late pregnancy or early lactation status would have resulted in very few animals requiring treatment being missed. The use of conjunctival mucous membrane colour scoring in this way provided a valuable insight of the general health status of the peri-urban goats, to create opportunities for planned animal health management to improve productivity. The efficacy of albendazole treatment was poor, putatively due to drug resistance, or poor drug bioavailability in goats. In summary, our study shows opportunities for better production efficiency in peri-urban goats, and demonstrates the value of simple clinical diagnostic indices as decision support tools in planned animal health management.

Nanoparticles in pregnancy: the next frontier in reproductive therapeutics.

BACKGROUND: Nanotechnology involves the engineering of structures on a molecular level. Nanomedicine and nano-delivery systems have been designed to deliver therapeutic agents to a target site or organ in a controlled manner, maximizing efficacy while minimizing off-target effects of the therapeutic agent administered. In both reproductive medicine and obstetrics, developing innovative therapeutics is often tempered by fears of damage to the gamete, embryo or developing foetus or of negatively impacting a woman's reproductive potential. Thus, nanomedicine delivery systems may provide alternative targeted intervention strategies, treating the source of the disease and minimizing long-term consequences for the mother and/or her foetus. OBJECTIVE AND RATIONALE: This review summarizes the current state of nanomedicine technology in reproductive medicine and obstetrics, including safety, potential applications, future directions and the hurdles for translation. SEARCH METHODS: A comprehensive electronic literature search of PubMed and Web of Science databases was performed to identify studies published in English up until February 2020. Relevant keywords were used to obtain information regarding use of nanoparticle technology in fertility and gene therapy, early pregnancy complications (ectopic pregnancy and gestational trophoblastic disease) and obstetric complications (preeclampsia, foetal growth restriction, preterm birth and gestational diabetes) and for selective treatment of the mother or foetus. Safety of specific nanoparticles to the gamete, embryo and foetus was also investigated. OUTCOMES: Pre-clinical research in the development of nanoparticle therapeutic delivery is being undertaken in many fields of reproductive medicine. Non-hormonal-targeted nanoparticle therapy for fibroids and endometriosis may provide fertility-sparing medical management. Delivery of interventions via nanotechnology provides opportunities for gene manipulation and delivery in mammalian gametes. Targeting cytotoxic treatments to early pregnancy tissue provides an alternative approach to manage ectopic pregnancies and gestational trophoblastic disease. In pregnancy, nanotherapeutic delivery offers options to stably deliver silencing RNA and microRNA inhibitors to the placenta to regulate gene expression, opening doors to novel genetic treatments for preeclampsia and foetal growth restriction. Restricting delivery of teratogenic drugs to the maternal compartment (such as warfarin) may reduce risks to the foetus. Alternatively, targeted delivery of drugs to the foetus (such as those to treat foetal arrythmias) may minimize side effects for the mother. WIDER IMPLICATIONS: We expect that further development of targeted therapies using nanoparticles in a reproductive setting has promise to eventually allow safe and directed treatments for conditions impacting the health and reproductive capacity of women and for the management of pregnancy and serious pregnancy complications.

[Systemic treatment of metastasized thyroid cancer-approved treatments and new approaches]. / Systemtherapien bei metastasierten Schilddrüsenkarzinomen ­ zugelassene Therapien und neue Ansätze.

The treatment of radioiodine-refractory differentiated thyroid carcinoma (rrDTC) and medullary thyroid carcinoma (MTC) remains challenging. Based on phase III clinical studies, four multi-kinase inhibitors (MKI) are approved for the treatment of progressive thyroid cancer in Germany. The indications for starting systemic treatment remain a challenge as the diseases can be stable and asymptomatic over long periods of time. In contrast, MKI treatment, which slows the disease progression but is not curative, is often associated with side effects that can impair quality of life. For this reason, an aim is to develop more specific treatments with low off-target effects. In this context selective RET kinase inhibitors represent a promising new approach, which is currently tested intensively in clinical trials, e.g. for advanced symptomatic MTC.

Potentials of using milk performance data and FAMACHA score as indicators for Targeted Selective Treatment in Lacaune dairy sheep in Switzerland.

Targeted Selective Treatment (TST) is one approach to slow down the development of anthelmintic resistance. Its success is closely linked to the correct identification of animals in need of treatment. In dairy goats it has been proposed to use milk yield as TST indicator and to focus treatments on high yielding dairy goats. In dairy sheep the relationship between milk performance and infection with gastrointestinal nematodes (GIN) is not well known. The aim of this study was to investigate the relationship between milk yield and GIN infection in dairy sheep and based on this, to evaluate milk performance data as a potential TST indicator. Overall 1159 Lacaune ewes of 15 dairy sheep farms in Switzerland were included in the study. The ewes were phenotyped once between August and December 2019, when they were at least 70 days in milk (DIM). Individual faecal samples were taken from every ewe to determine the nematode egg concentration per gram faeces (EPG). In addition, the clinical parameters FAMACHA score and packed cell volume (PCV) were measured. Linear mixed models were used to analyse the effects of the collected parameters on EPG. EPG increased significantly with increasing test day milk yields (P = 0.002), indicating high yielding ewes to be less resistant to GIN infections than low yielding ewes. The effect was most pronounced in earlier lactation but remained within a moderate range. Overall, our results indicated the potential of using milk yield data of rather early lactation as TST indicator in dairy sheep. On farms with predominantly H. contortus the combination with FAMACHA might improve the correct identification of highly infected ewes, as FAMACHA was correlated with EPG (r = 0.37, P < 0.001).