Clinical Field Trial Research Articles

Velagliflozin, a once-daily, liquid, oral SGLT2 inhibitor, is effective as a stand-alone therapy for feline diabetes mellitus: the SENSATION study.

To investigate safety and effectiveness of velagliflozin oral solution as sole therapy in naïve and previously insulin-treated diabetic cats. 252 client-owned cats receiving ≥ 2 doses of velagliflozin; 214 (85%) naïve diabetics and 38 (15%) insulin-treated diabetics. Prospective, baseline-controlled, open-label clinical field trial. Cats received velagliflozin orally, once daily. Physical examinations and blood collections were performed days 0, 3, 7, 30, 60, 120, and 180. Data are median (range). Screening blood glucose (BG) was 436 mg/dL (272 to 676 mg/dL). On days 30, 60, 120, and 180, single BG after receiving velagliflozin was 153 mg/dL (62 to 480 mg/dL), 134 mg/dL (64 to 414 mg/dL), 128 mg/dL (55 to 461 mg/dL), and 125 mg/dL (77 to 384 mg/dL), respectively. Screening fructosamine was 538 µmol/L (375 to 794 µmol/L). On the same recheck days, fructosamine was 310 µmol/L (204 to 609 µmol/L), 286 µmol/L (175 to 531 µmol/L), 269 µmol/L (189 to 575 µmol/L), and 263 µmol/L (203 to 620 µmol/L). At day 180, 81% of 158 cats remaining had BG and/or fructosamine within reference ranges; 88.6% (124 of 140) and 87.7% (121 of 138) showed improvement in polyuria and polydipsia, respectively. Ketonuria developed in 35 cats (13.9%), including 18 (7.1%) that had ketoacidosis. Ketoacidosis was less common in naïve diabetic cats (11 of 214 [5.1%]) compared to insulin-treated diabetic cats (7 of 38 [18.4%]). At ketoacidosis diagnosis, 14 of 18 cats (77.8%) were euglycemic (ie, BG < 250 mg/dL). Most episodes of ketosis or ketoacidosis (30 of 35 [85.7%]) occurred within the first 14 days of treatment. Insulin-treated diabetic cats were less likely to complete the trial. No clinical hypoglycemia occurred. Velagliflozin improved glycemic parameters and clinical signs in diabetic cats. Velagliflozin provides an alternative to insulin as a stand-alone treatment of diabetic cats.

Efficacy and immunogenicity following dengue virus-1 human challenge after a tetravalent prime-boost dengue vaccine regimen: an open-label, phase 1 trial

Dengue human infection models (DHIMs) are important tools to down-select dengue vaccine candidates and establish tetravalent efficacy before advanced clinical field trials. We aimed to provide data for the safety and immunogenicity of DHIM and evaluate dengue vaccine efficacy. We performed an open-label, phase 1 trial at the University of Maryland (Baltimore, MD, USA). Eligible participants were healthy individuals aged 18-50 years who either previously received a tetravalent dengue purified inactivated vaccine prime followed by a live-attenuated vaccine boost (ie, the vaccinee group), or were unvaccinated flavivirus-naive participants (ie, the control group). Participants in the vaccinee group with detectable pre-challenge dengue virus-1 neutralising antibody titres and flavivirus-naive participants in the control group were inoculated with dengue virus-1 strain 45AZ5 in the deltoid region, 27-65 months following booster dosing. These participants were followed-up from days 4-16 following dengue virus-1 live virus human challenge, with daily real-time quantitative PCR specific to dengue virus-1 RNA detection, and dengue virus-1 solicited local and systemic adverse events were recorded. The primary outcomes were safety (ie, solicited local and systemic adverse events) and vaccine efficacy (ie, dengue virus-1 RNAaemia) following dengue challenge. This study is registered with ClinicalTrials.gov, number NCT04786457. In January 2021, ten eligible participants were enrolled; of whom, six (60%) were in the vaccinee group and four (40%) were in the control group. Daily quantitative PCR detected dengue virus-1 RNA in nine (90%) of ten participants (five [83%] of six in the vaccinee group and all four [100%] in the control group). The mean onset of RNAaemia occurred on day 5 (SD 1·0) in the vaccinee group versus day 8 (1·5) in the control group (95% CI 1·1-4·9; p=0·007), with a trend towards reduced RNAaemia duration in the vaccinee group compared with the control group (8·2 days vs 10·5 days; 95% CI -0·08 to 4·68; p=0·056). Mild-to-moderate symptoms (nine [90%] of ten), leukopenia (eight [89%] of nine), and elevated aminotransferases (seven [78%] of nine) were commonly observed. Severe adverse events were detected only in the vaccinee group (fever ≥38·9°C in three [50%] of six, headache in one [17%], and transient grade 4 aspartate aminotransferase elevation in one [17%]). No deaths were reported. Participants who had tetravalent dengue purified inactivated vaccine prime and live-attenuated vaccine boost were unprotected against dengue virus-1 infection and further showed increased clinical, immunological, and transcriptomic evidence for inflammation potentially mediated by pre-existing infection-enhancing antibodies. This study highlights the impact of small cohort, human challenge models studying dengue pathogenesis and downstream vaccine development. Military Infectious Disease Research Program and Medical Technology Enterprise Consortium and Advanced Technology International.

Prevention of umbilical outpouchings and mortality in pigs: Meloxicam, tying, cutting, and chlorhexidine versus amoxicillin or no treatment? A clinical field trial

BackgroundUmbilical outpouchings (UOs) are common in Danish pigs. Neonatal antibiotics are therefore used with the hope of reducing umbilical infections and subsequently UOs. However, the effect of neonatal antibiotics on preventing UO has been the subject of mixed conclusions, and secondly, treating all animals with antibiotics might exacerbate the development of antimicrobial resistance.This study analysed the effects of different treatments on the prevalence of umbilical outpouchings and mortality from birth to nursery unit. All treatment was on the day of birth. The groups were: a negative control group, an antibiotic group receiving amoxicillin, and an experimental group where the piglets had their umbilical cord disinfected with chlorhexidine, followed by tying and clipping, and lastly, injection with meloxicam. The pigs were examined six weeks after weaning, and all pigs that died during the study were autopsied.ResultsThere were 5494 pigs divided across the three groups. There were no statistically significant differences in UO prevalence between the groups: control 3.9%, antibiotic 4.2%, and experimental 4.0% (p = 0.87). The only variable affecting the prevalence of UOs in this study was sex with females being at higher risk. There were no statistically significant differences in mortality between the groups from birth until departure from the nursery unit: control 22.9%, antibiotic 21%, and experimental 21.4% (p = 0.33). The variables affecting mortality were sex, intrauterine growth restriction (IUGR), birth weight, and cross fostering. Males had higher odds of dying, as had piglets recorded with some degree of IUGR. Also, low birth weight increased the odds of dying for all weight quartiles compared to the fourth (the heaviest piglets > 1.6 kg), as well as cross fostering increased the odds ratio of dying.ConclusionsThis study found no significant differences in the prevalence of UOs and mortality following different treatments at birth. The study showed that the prevalence of UO and mortality was not reduced following the administration of amoxicillin or meloxicam in combination with disinfection and tying of the umbilical cord.

Impacts of visual impairment on pragmatic impairment: A systematic review and meta-analysis

Background Consideration for patients with visual impairment, from low vision to blindness, is an important part of building a barrier-free society. Some authors have elaborated that visual impairment can indeed lead to delayed development in theory of mind, thereby causing pragmatic knowledge deficiency. Verifying whether those with eye conditions have pragmatic impairment is an essential way for their clinical evaluation, intervention and rehabilitation. Objective We primarily carry out a meta-analysis of visual impairment from low vision to blindness and pragmatic impairment in people with low vision or blindness to verify visual impairment may cause pragmatic impairment. Data sources Electronic databases Pubmed, Medline, MesH, Psychinfo, Ovid, EBSCO and CNKI and the reference sections of previous reviews. Study eligibility criteria Studies were included when they built on primary data from clinical questionnaire surveys or field trials anywhere in the world, and when they reported impacts of visual impairment on social cognition, communication, skills, behavior and intelligence. In total, 25 original studies were included, in which 25735 people were evaluated. Results Statistically, visual impairments and pragmatic impairment exist correlation due to the significant p value(p = 0.0005 &lt; 0.05) in group and the subgroup sorted in the light of 18 years old (p &lt; 0.0001 and p = 0.003 &lt; 0.05). Psychologically, because people with visual impairment can not normally get non-verbal information, they can not get a complete pragmatic knowledge system. Pragmatic knowledge deficiency leads to abnormal in executive functions and development delay from the perspective of theory of mind, inducing pragmatic impairment. Therefore, visual impairment has an impact on pragmatic impairment. Conclusion The meta-analysis reveals robust evidence on the relationship of vision impairment and pragmatic impairment in children or adults. Such evidence may help to gradually improve the clinical evaluation, intervention and rehabilitation of these people.

To Mars and Beyond: Engineering Life as a Moral Duty

To Mars and Beyond: Engineering Life as a Moral Duty

Clinical field trial of parenteral amoxicillin for the treatment of clinical and subclinical mastitis in smallholder dairy farms in the upper region of Northern Thailand.

Mastitis, primarily caused by intramammary bacterial infection, is the most expensive disease in the global dairy industry due to its negative impact on milk composition and manufacturing properties. This study aimed to evaluate the efficacy of parenteral amoxicillin in the treatment of clinical and subclinical mastitis in smallholder dairy farms in Northern Thailand. A total of 51 cows with clinical and subclinical mastitis from dairy cooperatives in Lamphun and Chiang Mai provinces, Northern Thailand, were enrolled in this study. Conventional bacteriological procedures were applied to identify the causative bacteria in milk samples from these cows before and 7 days after treatment, and antibiotic susceptibility tests were conducted using the disk diffusion method for all bacteria isolated before treatment. All cows with mastitis were administered 15 mg/kg of amoxicillin (LONGAMOX®, Syva Laboratories SA, Spain) intramuscularly every other day for 3 days. Environmental streptococcal bacteria (Streptococcus uberis and Streptococcus spp.) were commonly isolated from infected quarters and were highly susceptible to amoxicillin (100%). The clinical efficacy of amoxicillin treatment for clinical mastitis cases was 80.43%, and the bacteriological efficacy was 47.82%, with opportunistic staphylococcal bacteria (coagulase-negative staphylococci) and contagious streptococcal bacteria (Streptococcus agalactiae) being the most sensitive microorganisms (100%). In subclinical mastitis cases, the bacteriological efficacy of parenteral amoxicillin was 70.45%, with environmental streptococcal bacteria (S. uberis) being the most (100%) sensitive microorganisms. Amoxicillin is highly efficacious and can be used to treat clinical and subclinical mastitis in dairy cows, particularly mastitis caused by environmental Streptococcus spp. These findings could be used to guide treatment regimens in veterinary practice in smallholder dairy farms in Thailand.

Efficacy of a medetomidine-vatinoxan combination drug (Zenalpha) in dogs – a clinical field trial

Introduction: The objective of this study was to confirm the effectiveness of Zenalpha when compared to dexmedetomidine in providing sedation and analgesia to facilitate clinical examinations and procedures.

Promising Antioxidative Effect of Berberine in Cardiovascular Diseases.

Berberine (BBR), an important quaternary benzylisoquinoline alkaloid, has been used in Chinese traditional medicine for over 3,000 years. BBR has been shown in both traditional and modern medicine to have a wide range of pharmacological actions, including hypoglycemic, hypolipidemic, anti-obesity, hepatoprotective, anti-inflammatory, and antioxidant activities. The unregulated reaction chain induced by oxidative stress as a crucial mechanism result in myocardial damage, which is involved in the pathogenesis and progression of many cardiovascular diseases (CVDs). Numerous researches have established that BBR protects myocardium and may be beneficial in the treatment of CVDs. Given that the pivotal role of oxidative stress in CVDs, the pharmacological effects of BBR in the treatment and/or management of CVDs have strongly attracted the attention of scholars. Therefore, this review sums up the prevention and treatment mechanisms of BBR in CVDs from in vitro, in vivo, and finally to the clinical field trials timely. We summarized the antioxidant stress of BBR in the management of coronary atherosclerosis and myocardial ischemia/reperfusion; it also analyzes the pathogenesis of oxidative stress in arrhythmia and heart failure and the therapeutic effects of BBR. In short, BBR is a hopeful drug candidate for the treatment of CVDs, which can intervene in the process of CVDs from multiple angles and different aspects. Therefore, if we want to apply it to the clinic on a large scale, more comprehensive, intensive, and detailed researches are needed to be carried out to clarify the molecular mechanism and targets of BBR.

Efficacy of a spot-on combination containing 10% w/v imidacloprid and 1% w/v moxidectin for the treatment of troglostrongylosis in experimentally infected cats

BackgroundParasitic bronchopneumonia in domestic cats in Europe, which can manifest with moderate to severe clinical signs, is frequently caused by Troglostrongylus brevior. Data on epizootiological and clinical relevance of cat troglostrongylosis have been published in the last decade but treatment options are still limited. Promising effectiveness data have been generated from clinical cases and field trials for a spot-on formulation containing 1% w/v moxidectin and 10% w/v imidacloprid (Advocate®, Elanco Animal Health). Therefore, two studies have been conducted to confirm under experimental conditions the efficacy of moxidectin 1% contained in Advocate® for the treatment of cat troglostrongylosis.MethodsSixteen and 20 cats experimentally infected with T. brevior were included in two separate studies, i.e., Study 1 and 2, respectively. Cats were infected with T. brevior third-stage larvae via gastric tube. In both studies cats were randomized to untreated (control, Group 1) and treatment (Group 2) groups. In Study 1 and Study 2, the two groups comprised eight and 10 cats each. Treated cats received Advocate® spot-on twice at a 4-week interval. The primary efficacy criterion was the number of viable adult T. brevior counted at necropsy. Throughout the trial, the fecal shedding of first-stage larvae (L1) was assessed in treated and untreated control cats.ResultsThe experimental model was successful in both studies, as all cats started shedding T. brevior L1 within 25 days post-infection. At necropsy, T. brevior adults were found in 4/8 and 4/10 cats of the control groups in Study 1 and 2, respectively, while none of the treated cats harbored adult worms. The necropsy worm counts in controls did not meet relevant guideline requirements for adequacy of infection, with fewer than six infected cats in the control groups, thus limiting conclusions on treatment efficacy. The fact that 6/8 and 8/10 control cats in Study 1 and 2, respectively, shed L1 up to necropsy while larval shedding ceased in all treated animals after the first treatment provides supporting evidence on the level of efficacy. No remarkable adverse events were recorded in the two studies.ConclusionThese results indicate that Advocate® spot-on is a safe and effective option for treating cats infected by T. brevior.Graphical

Antigen-Based Point of Care Testing (POCT) for Diagnosing SARS-CoV-2: Assessing Performance.

Currently, the most accurate way to diagnose an active SARS-CoV-2 (COVID-19) infection is through detection of viral RNA using reverse transcription polymerase chain reaction (RT-PCR) test. While RT-PCR tests are the most sensitive for identifying infection, there are significant limitations, such as global access to sufficient test kits, turnaround times (TAT) from specimen collection to test result is often greater than 24h and the need for skilled operators in accredited laboratories requiring specialized equipment. A rapid test performed at the point of care (POC) could provide a result within an approximate time of 30min post specimen collection, be performed by a health care worker and comprise a simple workflow, improving both turnaround time and potentially decreasing costs (e.g., transport, cold-chain, skilled laboratory staff, complex equipment). Determining the performance of SARS-CoV-2 RT-PCR tests is, however, easier to assess than antigen-based POCT, as residual clinical specimens (swabs in universal transport media [UTM]) are readily available in laboratory environments, and do not require patient informed consent. Evaluating the performance of POCT requires informed-consent driven studies, with patients required to provide a standard of care specimen as well as study evaluation specimens, which is often not acceptable as nasopharyngeal swabbing can be invasive, clinical field trials are costly and time consuming. Many institutions and regulatory bodies also require preliminary data prior to use in field settings. Therefore, we have developed a method to determine the performance of antigen based POCT that can be used by implementers in national healthcare programs, regulators and rapid test developers. The method investigates both quantitative and qualitative parameters, with the latter providing insights into the capability for implementation and national program uptake.

The Impact of Integrated Support and Context on Treatment Implementation and Child Outcomes Following Behavioral Consultation.

Assuring treatment plan implementation following consultation is critically important because implementation is strongly related to outcomes. Treatment implementation has been hypothesized to be influenced by both the nature of the follow-up support provided and contextual variables. However, studies to date have not examined both issues while directly measuring implementation. This study examined treatment implementation following consultation for 48 teachers in public schools who had referred a student for intervention services in a randomized clinical field trial. Participating teachers in the experimental group received Integrated Support (IS). IS includes social influence, planning, and performance feedback elements. IS was compared to weekly follow-up meetings alone. Treatment implementation and child outcomes were markedly superior for IS as compared to weekly follow-up. Three school climate factors were found to be correlated with treatment implementation for the IS group, but not the weekly follow-up group. Participants rated treatment implementation, treatment acceptability, and consultant effectiveness positively and similarly across conditions. The implications of these findings for future work examining school culture, consultation and intervention are discussed.

Efficacy of fipronil/(S)-methoprene/eprinomectin/praziquantel (Broadline\xae) against Thelazia callipaeda in naturally infected cats

BackgroundThe present clinical field trial was conducted to assess the efficacy of a broad-spectrum parasiticide spot-on formulation containing eprinomectin (Broadline®) against Thelazia callipaeda eyeworm in naturally infected cats.MethodsFifteen privately owned cats harboring at least one live adult T. callipaeda were included in the study. Cats were randomly allocated to an untreated control group of seven cats or to a Broadline®-treated group of eight cats. Cats were treated on Day 0; ocular examinations were performed at inclusion and on Days 7 and 14; eyeworms were recovered and counted on Day 14. The primary efficacy assessment was based on group comparison of number of T. callipaeda on Day 14.ResultsSeven days after treatment, six of eight treated cats were negative for eyeworm infection per visual examination, and on Day 14 no eyeworms were found in the treated cats while the seven untreated cats were still infected (geometric mean: 1.97). All cats had inflammatory ocular signs at inclusion; on Day 14, five of eight treated cats had recovered while all untreated control cats were still symptomatic. All collected parasites were confirmed to be T. callipaeda by morphology and molecular characterization.ConclusionsA single treatment with Broadline® provided 100% efficacy against feline thelaziosis and improved related ocular inflammation signs.Graphical abstract

The Importance of Sphingosine Kinase in Breast Cancer: A Potential for Breast Cancer Management

Breast cancer management includes a combination of surgery, radiation therapy, and chemotherapy. While this management has proven effective, it is not perfect. To expand the umbrella of management to resistant breast cancer tumors, researchers have explored the idea of sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) as a potential target for treatment. In this article, we review the mechanism of the sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) axis along with its effect on the tumor microenvironment (TME) and compounds that have been studied inhibiting the SphK/S1P axis. We searched for relevant articles in the last five years in Medline and PubMed Central. Inclusion criteria, exclusion criteria, and quality checklists were applied to identify the most relevant articles. We compiled the information that has been summarized in the respective tables and figures provided in this review. The metabolism of sphingolipids was summarized, followed by the SphK/S1P upregulation in breast cancer cells. The variety of effects by upregulation of SphK led to an increase in inflammation, growth, and metastasis in breast cancer tumors. The increase in S1P also impacted the TME, including the cells and surrounding tissue, allowing the breast tumors to thrive. The final point made was a summary of the compounds and drugs that inhibited the SphK/S1P axis. They have proven their effectiveness and show even greater efficacy in combination with docetaxel and doxorubicin in preclinical studies. In conclusion, what is known about the SphK/S1P axis within breast cancer cells is immense but incomplete as we summarize what is known so far. Having a complete picture will allow a faster transition to application in the clinical field but clinical trials have not commenced as of yet.

A Mobile Tele-Ophthalmology System for Planned and Opportunistic Screening of Diabetic Retinopathy in Primary Care

Diabetic Retinopathy is a complication of diabetes that can cause severe vision impairment or even blindness. The condition is treatable in early stages, but it often progresses asymptomatic and undetected. Once the symptoms become noticeable, damage in the retina might already be permanent, thus many countries have implemented retinal imaging screening programmes for their diabetic population. However, existing screening programmes are not reaching all patients, and Diabetic Retinopathy stands as a leading cause of preventable blindness in the active population. We contend that the existing technological infrastructures and clinical processes may be hindering the coverage of Diabetic Retinopathy screening programmes. This paper presents EyeFundusScopeNEO, a Tele-Ophthalmology system based on a screening information system and a mobile fundus camera, which shall support opportunistic and planned screening in primary care, using cameras that are handheld, non-invasive, avoid drug-induced pupil dilation, are usable by clinicians who are not specialised in Ophthalmology, and that cost a fraction of existing table-top fundus cameras. Preliminary studies indicate the potential of the system to increase the reach of screening programmes and clinical research field trials are under preparation.

Potential of Artesunate in the treatment of visceral leishmaniasis in dogs naturally infected by Leishmania infantum: Efficacy evidence from a randomized field trial.

Leishmaniasis is among the world’s most neglected diseases. Dogs are the main reservoirs/hosts of Leishmania infantum, causative agent of both canine and human visceral leishmaniosis. Canine leishmaniasis (CanL) represents a public health problem as one of the most prevalent zoonotic diseases worldwide. Current therapeutics present drawbacks; thus, there is a need for more effective, safer, and cheaper drugs. The aim of this study was to evaluate and to compare the efficacy of oral administration of artesunate or meglumine antimoniate/allopurinol in dogs with clinical leishmaniasis. Forty-two dogs with naturally occurring clinical leishmaniasis were included in this open-label, simple randomized positive-control clinical field trial with 6 months of follow-up. Dogs received meglumine antimoniate 100 mg/kg/day and allopurinol 30 mg/kg/day for 28 days (control group, n = 26) or artesunate 25 mg/kg/day for 6 days (test group, n = 16). The animals were evaluated for their clinical evolution, parasite load (by qPCR) and humoral response at different time points: 0, 30, 90, and 180 days after treatment. Data analyses showed a significant improvement in both groups in clinical scores, parasitemia and antibody titers after treatment. Compared to the control group, the artesunate group showed significantly lower clinical score (P = 0.0001), lower parasitemia (P = 0.0001) and antibody titers after 6 months of follow-up. Compared to baseline values, a rapid, significant reduction (P < 0.012) in antibody levels, 2.28- versus 3.04-fold for the control versus artesunate groups, respectively, was observed 30 days after treatment. Antibody levels continued to decrease further in the artesunate group, where 58% of cases became seronegative at the 6-month follow-up. All qPCR-positive dogs were negative after treatment with artesunate, while 14.3% remained positive with the appearance of two new cases in the control group. Artesunate was well tolerated, and no side effects were recorded. Treatment failures were similar in both groups with 27.27% (6/22), including 18.18% (4/22) mortality in the control group, versus 26.66% (4/15), including 13.33% (2/15) mortality in the artesunate group. This is the first report showing the potential of artesunate in the treatment of dogs with clinical leishmaniasis. Artesunate showed higher efficacy than the current first-line treatment for CanL without any adverse effects. It could be a good alternative chemotherapy for CanL, and may be considered for further studies in human leishmaniases. Further clinical trials are needed to confirm these findings, to determine if there are relapses after treatment and if dogs remain infective to sandflies, to define the ideal therapeutic dosage and duration of treatment with artesunate.

Drinking a structured water product on markers of hydration, airway health and heart rate variability in Thoroughbred racehorses: a small-scale, clinical field trial

Racehorses in training are in situations of repeated stress that may have effects on hydration and health, including airway health. The main hypothesis of this descriptive study was that daily consumption of a structured water (SW) product for 4 weeks will result in improved hydration, reduced markers of upper airway health concerns and increased heart rate variability. Two groups of Thoroughbred racehorses matched for physiological, training and racing attributes were studied for 4 weeks. One group (n = 17) received 10 L (~15%) of their daily water as SW (followed by ad libitum filtered deep well water) and the control group (n = 15) only filtered deep well water. Duplicate (two separate days) blood samples and bioelectrical impedance analysis (BIA) measures were obtained at baseline, 2 and 4 weeks. Hydration was assessed using BIA. The upper airway was assessed by nasopharyngeal endoscopy at baseline within 60 minutes of breezing (weekly near-race gallop pace). On weekly breeze days heart rate was recorded at rest, during exercise and recovery and data were analysed for heart rate variability. Compared to controls, horses drinking SW showed: (a) increased hydration by 2 weeks that was sustained to 4 weeks; (b) upper airway health (less mucous and less trace bleeding) post-breezing; and (c) increased heart rate variability (more restorative autonomic response) at rest. There were no performance benefits, no adverse events occurred, and blood hematological and biochemistry parameters were normal throughout. It is concluded that drinking 10 L daily of SW increased hydration and may have conferred some wellness benefits.

Experimental assessment of permethrin-fipronil combination in preventing Leishmania infantum transmission to dogs under natural exposures

Canine vector-borne disease transmission can be reduced with regular use of repellent insecticides. The objective of this year-long experimental study was to assess the efficacy of a topical formulation of fipronil/permethrin (Frontline Tri-Act®) in preventing transmission of Leishmania infantum by sandflies. This clinical field trial was conducted in Xanthi (Northern Greece), an area highly endemic for canine leishmaniosis, from April 2018 to March 2019. Forty purpose-bred Beagle dogs, testing negative for L. infantum prior to study initiation, were enrolled in the study, which consisted of three phases: Phase 1 (field exposure phase) took place from Day 0–196. The dogs were randomly allocated to two groups, group 1 (sham-treated topically with sterile water) and group 2 (treated topically with Frontline Tri-Act®). Dogs in both groups were housed in two subunits of an open-air kennel for a period of 7 months, spanning the Leishmania transmission season. All dogs were treated or sham-treated on Days 0, 28, 56, 84, 112, 140 and 168. Clinical examinations, PCR analysis of conjunctival swabs, and serological tests were performed on a monthly basis. Sandflies were collected every 2 weeks, during a 12-h period overnight using light traps. Each collection was placed in a container and kept refrigerated until speciation and PCR analysis could be performed. In the second phase of the study, from Day 197 to 252, the dogs were moved into a protected environment (insect-proof protected environment phase). CDC light traps were activated every 2 weeks inside and outside the kennels to ensure the vector-free status of the facility. Monthly clinical examinations, including PCR analysis of conjunctival swabs, and serological tests continued. At the end of the phase 2, bone marrow samples were collected on all dogs. Phase 3 (the final post-winter check) took place from Day 253 to 350. Dogs were released and adopted by individual private owners on Day 253. Follow up analyses included blood collection for SNAP tests and conjunctival swaps for PCR analysis on Days 304 and 350. Additionally, bone marrow collections were also performed on Day 350.Presence of sandflies was observed only in the phase 1 exposure period, and 1714 sandflies were collected (1427 females and 287 males). Two species were identified, Phlebotomus perniciosus var. tobbi and Phlebotomus neglectus. Out of the 62 pooled samples of sandflies assessed by PCR, three were considered positive (4.8 %). By the end of the study, 35 % of the Group 1 dogs (7/20) became positive based on PCR (conjunctival swab and bone marrow) and 30 % (6/20) based on SNAP/IFAT and ELISA tests, while all the dogs in the Frontline Tri-Act® treated group 2 remained negative for all tests (G1 vs G2, p=0.008). All tests identified the same positive animals, and PCR allowed the detection of one additional infected dog. This clinical field trial demonstrated that monthly administration of Frontline Tri-Act® to dogs exposed to Leishsmania infection in a high endemic area provided 100 % preventive efficacy against transmission of L. infantum.

Engineering Steps for Mobile Point-of-Care Diagnostic Devices.

Mobile phone technology is a perfect companion for point-of-care diagnostics as they come equipped with advanced processors, high resolution cameras, and network connectivity. Despite several academic pursuits, only a few mobile phone diagnostics have been tested in the field, commercialized or achieved regulatory approval. This review will address the challenges associated with developing mobile diagnostics and suggest strategies to overcome them. We aim to provide a resource for researchers to accelerate the development of new diagnostics. Our Account includes an overview of published mobile phone diagnostics and highlights lessons learned from their approach to diagnostic development. Also, we have included recommendations from regulatory and public health agencies, such as the U.S. Food and Drug Administration and World Health Organization, to further guide researchers. We believe that the development of mobile phone point-of-care diagnostics takes place in four distinct steps: (1) Needs and Value Assessment, (2) Technology Development, (3) Preclinical Verification, and (4) Clinical Validation and Field Trials. During each step, we outline developmental strategies to help researchers avoid potential challenges. (1) Researchers commonly develop devices to maximize technical parameters such as sensitivity and time which do not necessarily translate to increased clinical impact. Researchers must focus on assessing specific diagnostic needs and the value which a potential device would offer. (2) Often, researchers claim they have developed devices for feasible implementation at the point-of-care, yet they rely on laboratory resources. Researchers must develop equipment-free devices which are agnostic to any mobile phone. (3) Another challenge researchers face is decreased performance during field evaluations relative to initial laboratory verification. Researchers must ensure that they simulate the field conditions during laboratory verification to achieve successful translation. (4) Finally, proper field testing of devices must be performed in conditions which match that of the final intended use. The future of mobile phone point-of-care diagnostic devices is bright and has the potential to radically change how patients are diagnosed. Before we reach this point, researchers must take a step backward and focus on the first-principles of basic research. The widespread adoption and rapid scaling of these devices can only be achieved once the fundamentals have been considered. The insights and strategies provided here will help researchers avoid pitfalls, streamline development and make better decisions during the development of new diagnostics. Further, we believe this Account can help push the field of mobile diagnostics toward increased productivity, leading to more approved devices and ultimately helping curb the burden of disease worldwide.

Correction: Evaluating the impact of meloxicam oral suspension administered at parturition on subsequent production, health, and culling in dairy cows: A randomized clinical field trial.

[This corrects the article DOI: 10.1371/journal.pone.0209236.].

Evaluation of an 11.2% spinetoram topical spot-on solution for the control of experimental and natural flea (Ctenocephalides felis) infestations on cats in Europe

Spinetoram is the newest member the spinosyn-class of natural products to be commercialized for flea control on cats in the United States under the tradename Cheristin® for cats. This report describes results from two laboratory studies and a multi-center clinical field trial designed to confirm the efficacy of a topical spot-on solution containing spinetoram (11.2% w/w, 130 mg/mL) against European strains of the cat flea, Ctenocephalides felis.In the laboratory studies, cats were allocated to one of two treatment groups of eight animals each: negative control (mineral oil) or spinetoram, both applied as a topical spot-on at the base of the skull on Day 0. Cats were infested with ∼100 newly emerged, unfed adult fleas on Days −2 or −1, 7, 14, 21, 28 and 35. To calculate efficacy, fleas were counted and removed 48 h after treatment, and 48 h after each subsequent infestation through week 5. Spinetoram treatments provided 100% efficacy through at least day 16 and ≥ 97% efficacy (arithmetic mean) for one month.For the field trial, 23 clinics from Northern and Southern Europe participated in the study that compared the effectiveness and safety of spinetoram and fipronil/(S)-methoprene treatments over a period of two months. There were 258 and 248 evaluable efficacy cases for month 1 and month 2, respectively, with 300 total evaluable cases for safety. Treatments were administered on Day 0 and again on Day 30 (±3 days). The effectiveness of treatments was calculated based on reduction in live flea counts on Days 14, 30, 44 and 60 (±3 days) relative to flea counts obtained on Day 0. Efficacy (geometric mean percent flea reduction) on Days 14, 30, 44 and 60 was 97.0%, 95.0%, 99.3% and 99.1% for spinetoram, respectively, and 86.1%, 80.9%, 92.4% and 92.3% for fipronil/(S)-methoprene, respectively. Spinetoram was deemed non-inferior at all intervals and superior to fipronil/(S)-methoprene at Days 30 and 60. Clinical signs of flea allergy dermatitis (FAD) were markedly improved following spinetoram treatment, as demonstrated through statistically significant reductions in severity of FAD scores for most of the clinical signs when compared to fipronil/(S)-methoprene treatment. There was a lower overall adverse event incidence rate for spinetoram (5.1%) versus fipronil/(S)-methoprene treatment (11.5%).