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The objective of this controlled study was to determine the anthelmintic efficacy of eprinomectin 5% w/v extended-release injection (Eprinomectin ERI; LONGRANGE®, Boehringer Ingelheim Animal Health) against primarily ovine-adapted gastrointestinal strongylid nematode (GIN) parasites in naturally infected young cattle. Eighteen calves which grazed on a sheep-dominated mixed sheep-cattle farm were randomly allocated into two equal groups (saline [control] or Eprinomectin ERI, administered each at 1 mL/50 kg body weight once subcutaneously), treated and euthanized 14 days thereafter for a differential GIN count. Ten species of strongylid nematodes were recovered from the control calves (ovine-adapted Haemonchus contortus, Teladorsagia circumcincta, Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battus, Chabertia ovina; bovine-adapted Ostertagia ostertagi, Cooperia oncophora, Nematodirus helvetianus; 'generalist' Trichostrongylus axei). Adult GIN counts ranged from 1,540 to 5,244 for the control calves and from zero to 110 for the Eprinomectin ERI-treated calves. Accepting the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products anthelmintic guidelines criteria on adequacy of infections to be demonstrated in the control animals, this study showed that Ch. ovina, C. curticei, H. contortus, N. battus, T. axei, and T. colubriformis were reduced significantly (p 0.0001) by ≥ 98.7% in the animals treated with Eprinomectin ERI. In conclusion, Eprinomectin ERI treatment was efficacious against a range of ovine-adapted nematode parasites in naturally infected young cattle.

In an effort to generate data for regulatory purposes on the therapeutic efficacy of eprinomectin 5% w/v extended-release injection (Eprinomectin ERI) (LongRange®, Boehringer Ingelheim) against infections of immature and adult stages of some nematode species (or stages) which are generally less common or predominantly seen in younger cattle, nine studies (minimum two per parasite and stage) were conducted in the USA and Germany. A total of 218 young cattle were included in seven experimentally induced infection studies (180 animals) and two studies with naturally acquired nematode infections (38 animals), which were compliant with WAAVP and VICH guidelines. In each study, cattle were randomly assigned into groups which received 1 mL per 50 kg body weight of either saline (controls) or Eprinomectin ERI (equivalent to 1 mg eprinomectin per kg body weight) via subcutaneous injection when the parasites were developing fourth-stage larval (L4) or adult nematodes. Following necropsy and parasite recovery, percentage efficacy was calculated based on the comparison of geometric mean nematode counts of the Eprinomectin ERI- vs. the saline-treated animals. Eprinomectin ERI-treated cattle had significantly (p 0.05) lower counts of each species and stage of nematodes than the controls. Eprinomectin ERI treatment was demonstrated to be efficacious ( 90%) against L4 and adult Bunostomum phlebotomum and Nematodirus helvetianus; against L4 Haemonchus placei, Oesophagostomum radiatum, and Trichostrongylus colubriformis; and against adult H. contortus. Percentage efficacy against L4 H. contortus was variable (69.6 to 100%). All treatments were well accepted, and no treatment-related health problems were observed in any study.

The efficacy of the topical and injection formulations of eprinomectin (0.5 % w/v topical solution, EPRINEX®; 5 % w/v extended-release injection, LONGRANGE®; Boehringer Ingelheim) against larval and adult stages of the rare bovine large intestine nematodes Chabertia ovina and Oesophagostomum venulosum was evaluated in one Good Clinical Practice study compliant to World Association for the Advancement of Veterinary Parasitology and International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products anthelmintic guidelines. Forty nematode naïve induced infected Brown Swiss calves were allocated into five groups of eight completely at random. Inoculation with isolates obtained in Germany was staggered so that the parasites of the two species were, when the treatments were administered, concurrently fourth-stage larval or adult nematodes, respectively. One group served as untreated control, two groups each received eprinomectin 0.5 % w/v topical solution or eprinomectin 5 % w/v extended-release injection per product label. Animals were necropsied at one and the same day (corresponding to six weeks or two weeks after administration of treatments against fourth-stage larval or adult nematodes) for parasite recovery and count. Both C. ovina (range, 39-604) and O. venulosum (range, 3-23) were recovered from all eight controls while among the 32 calves which were administered topical solution or extended-release injection eprinomectin, only a single C. ovina specimen was isolated from one animal which received the injection product when the nematodes were adult. Eprinomectin treatments were 99.9 % effective against fourth-stage larval or adult C. ovina and O. venulosum nematodes (p 0.001 at α = 0.05). All animals accepted the treatments well. No adverse events or other health problems were observed in the study animals.

Advances in ultrathin, skin-like electronics lead to wearable devices for continuous, noninvasive blood flow monitoring., Continuous monitoring of variations in blood flow is vital in assessing the status of microvascular and macrovascular beds for a wide range of clinical and research scenarios. Although a variety of techniques exist, most require complete immobilization of the subject, thereby limiting their utility to hospital or clinical settings. Those that can be rendered in wearable formats suffer from limited accuracy, motion artifacts, and other shortcomings that follow from an inability to achieve intimate, noninvasive mechanical linkage of sensors with the surface of the skin. We introduce an ultrathin, soft, skin-conforming sensor technology that offers advanced capabilities in continuous and precise blood flow mapping. Systematic work establishes a set of experimental procedures and theoretical models for quantitative measurements and guidelines in design and operation. Experimental studies on human subjects, including validation with measurements performed using state-of-the-art clinical techniques, demonstrate sensitive and accurate assessment of both macrovascular and microvascular flow under a range of physiological conditions. Refined operational modes eliminate long-term drifts and reduce power consumption, thereby providing steps toward the use of this technology for continuous monitoring during daily activities.

Continuous infrared imaging revealed transient changes in forearm temperature during arterial occlusion, reperfusion, and recovery in a healthy subject group. Processing the imaging data with the k-means algorithm further revealed reactive vascular sites in the skin with rapid or delayed temperature amplification. The observed temporal and spatial diversity of blood-flow-derived forearm temperature allow consideration of thermal-imaging guided placement of skin sensors to achieve enhanced sensitivity in monitoring of skin hemodynamics.

The hallmark manifestation of homozygous sickle cell disease (SCD) is acute pain. The underlying etiology is unknown. It is believed that hypoxia induces changes in erythrocyte shape and produces microvasculature occlusion by sickled red cells. Vascular occlusion is believed to represent the event inducing tissue hypoxia, reperfusion injury and pain. Studies have only recently characterized pain responses to experimental stimuli in rodents and humans with SCD using quantitative sensory testing (QST). SCD is characterized by thermal and mechanical sensitivity, and there is evidence of central sensitization (heightened sensitivity to pain) from QST, temporal summation and functional MRI studies. However, the effect of hypoxia upon nociception has not been studied despite the need for hypoxia to induce sickle hemoglobin polymerization. The ischemic tourniquet pain test is a QST used to investigate nociception. It was the first QST to demonstrate opioid analgesia. While it is assumed that the resulting pain is due to hypoxia, no studies have demonstrated the degree of hypoxia needed to produce pain. Methods: Thirty adults with SCD and 30 age and sex matched 30 controls underwent the ischemic pain test. A pneumatic cuff was inflated around the upper arm to induce forearm hypoxia, and the time from cuff inflation to first reported pain (pain threshold) and until pain became intolerable (pain tolerance) was measured. Pain was quantified on a 20 point scale. Time to pain threshold and tolerance were the primary end points. Testing was repeated after a washout period in a subset of the initial subjects: 18 SCD patients and 22 controls. Repeat testing proceeded with a 15 minute observation period followed by the ischemic pain test with the time and pain score recorded at threshold and tolerance. Subjects were monitored after cuff deflation during recovery with pain scores obtained at 30 seconds, then every minute for 5 minutes and finally every 3 minutes over a total recovery period of 20 minutes. Skeletal muscle tissue oxygenation at the thenar eminence was measured continuously with a near infrared spectroscopy (NIRS) monitor (OxiplexTS; ISS, Champaign, IL). Results: SCD subjects reached the pain threshold at a mean of 6.44 versus 11.57 minutes in controls (p=0.07). Time to pain tolerance was significantly different (SS 11.29 versus controls 19.59 minutes; p=0.004). Both groups reported identical pain scores. By stepwise linear regression, SCD (p=0.002) and gender (p=0.0008) were associated with time to pain tolerance (r2=0.29), while recent opioid use and pain crisis frequency were not. Because these results demonstrated that SCD adults reach tolerance more rapidly than controls, we sought to determine if this difference was due to tissue hypoxia. Pain scores with repeat testing were not significantly different at threshold or tolerance. However, pain score curves over testing and recovery were significantly different (p=0.003, Fig 1A). SCA had pain above baseline after 11 minutes of recovery (p=0.02) suggesting a persistent pain response compared to controls. Oxyhemoglobin and deoxyhemoglobin from NIRS were not different between groups at the primary endpoints (Fig 1B and 1C). StO2 (% tissue oxygenation, Fig 1D) at both threshold and tolerance was not different between SCD and controls, suggesting that the onset and maximal level of pain during this QST is defined an StO2 thresholds 40% common to sickle cell patients and controls. However, oxyhemoglobin, deoxyhemoglobin and StO2 had already recovered to baseline by the time the pain was evident (Fig 1B, 1C and 1D). Conclusions: Adults with SCD reach hypoxia induced, experimental pain earlier than NVs. Time to maximal pain is associated with SCD and sex. NIRS showed that pain tolerance occurred at a uniform tissue oxygenation threshold indicating hypoxia is the primary determinant for sensing acute pain. However, persistent SCD pain was independent of tissue oxygenation, and could be explained by the presence of peripheral or central sensitization. These data suggest that SCD pain treatment may require improved oxygen delivery to affected tissues and analgesics. Figure 1. Nociceptive and NIRS responses to ischemic pain testing in adults with sickle cell anemia. Figure 1. Nociceptive and NIRS responses to ischemic pain testing in adults with sickle cell anemia. Disclosures No relevant conflicts of interest to declare.

The clinical hallmark of sickle cell anemia is the vaso-occlusive pain crisis. Although the exact cause for severe vaso-occlusive painful events is unknown, sickle cell microvasculature occlusion is thought to be the proximate cause producing tissue hypoxia, reperfusion injury and acute pain. Endothelial dysfunction is a prominent characteristic of sickle cell anemia, and it is unclear to what extent this abnormal vascular response contributes to vaso-occlusion and pain. We sought to evaluate the effects of hypoxia on sickle cell pain by performing a forearm ischemic pain test as a potential in vivo model for vaso-occlusion. We hypothesized that sickle cell anemia patients would tolerate a shorter period of ischemia before reaching pain tolerance. We further hypothesized that sickle patients would show more hypoxia and increased vasodilation. Thirty adults with sickle cell anemia were recruited and matched by age and sex to 30 normal volunteers. We first performed a timed ischemic pain test with brachial artery occlusion until subjects first reported pain (pain threshold) and until maximum pain tolerated (pain tolerance). Sickle cell subjects first reported pain at 411 vs. 589 s for normal volunteers (mean, p=0.07). Occlusion time to pain tolerance was significantly shorter for sickle cell patients (637 vs. 918 s, mean, p=0.004). Despite this difference, both groups reported nearly identical pain scores at threshold and tolerance. Stepwise linear regression for all subjects against 8 variables likely to influence pain showed sickle status (p=0.002) and gender (p=0.0008) were independently associated with time to tolerance, supporting our initial hypothesis. Testing with continuous physiological monitoring was next repeated in sub-groups of 7 sickle cell and 9 normal subjects in an effort to understand the association between ischemia and pain progression. Before, during, and after brachial artery occlusion, oxygenated/deoxygenated hemoglobin concentration and tissue oxygen saturation were continuously monitored with near-infrared spectroscopy at the thenar eminence. We also recorded cutaneous blood flow with a Laser Speckle Contrast Imager (FLPI-2) in the volar aspect of forearm and continuous blood pressure and pulse in the contralateral arm. Monitoring was performed during steady state prior to occlusion (15 min), during occlusion until pain tolerance, and during recovery (20 min). At steady state, sickle cell subjects had higher median heart rate (68 vs. 62 bpm, p=0.05) and cutaneous blood flow (81.8 vs. 46.8 a.u., p Overall, sickle cell subjects have significantly lower steady state tissue oxygenation, but they are less tolerant of hypoxia and develop pain at higher oxygenated hemoglobin levels during ischemia. Despite higher oxygenated hemoglobin during ischemia, sickle cell subjects have a significantly higher absolute decline in blood flow during occlusion, suggesting an altered hypoxic response compared to controls. This might suggest a hypersensitive hypoxic pain response, possibly due to the presence of chronic pain, and altered oxygen sensing. The ischemic pain test is a potential in vivo model for early stage trials of drugs that alter either acute pain transmission or oxygen delivery to tissues. Disclosures No relevant conflicts of interest to declare.

The efficacy of an oral formulation of ivermectin plus praziquantel in the reduction of nematode and cestode egg counts in horses was assessed in 273 horses under field conditions at 15 sites in North America (n = 6) and Europe (n = 9). Horses were confirmed by fecal examination to have natural infections of strongyles (100%) and tapeworms (76%). Replicates of four horses were formed at each site, and in each replicate three animals received ivermectin (0.2 mg/kg body weight) plus praziquantel (1 mg/kg body weight) oral paste and one animal remained untreated or received vehicle paste. Fecal samples were collected for fecal nematode and cestode egg counting before and 7, 8, 9, 14, 15, and 16 days after treatment. Horses treated with ivermectin plus praziquantel oral paste had significantly (P.01) lower posttreatment strongylid and cestode egg counts (reductions of 98% or more) than controls. Combined site analyses revealed that 95% or 96% of the horses positive for cestode eggs before treatment that were treated with ivermectin plus praziquantel were negative for cestode eggs at each posttreatment fecal examination. No adverse reactions attributable to ivermectin plus praziquantel oral paste treatments were observed. The results of the studies demonstrated that ivermectin plus praziquantel paste was highly effective in reducing egg shedding by gastrointestinal nematodes and cestodes, and no adverse reactions were observed in horses treated under field conditions.

Unfortunately, African American men have a higher incidence of and a higher mortality rate for prostate cancer than White men but are less likely to participate in prostate cancer screening. This correlational survey research identifies predictors for participation in a free prostate cancer screening in 179 men, 64% of whom are African American. Each man was invited to see his personal physician for a free prostate cancer screening following a prostate cancer educational program given at his worksite. Forty-seven percent of the African American men went to their personal physician following the educational program and received a digital rectal examination (DRE) and a prostate specific antigen (PSA) screening. In the original cohort of educational program attendees, only 16% of the African Americans had obtained a DRE in the previous 12 months. However, 44% subsequently did participate in free DRE screening. Similarly, only 6% of the African American men had received a PSA screening in the previous 12 months, yet 42% obtained a PSA screening after the educational program, a sevenfold increase. Implications for allocating limited resources for education and screening to the high-risk group of African American men are discussed. This study's model of a prostate cancer educational program at worksites followed by attendees visiting their personal physician for screening could be replicated throughout the United States to increase African American men's participation in prostate cancer screening.