Effect of water sulfate and dietary bismuth subsalicylate on feed and water intake, ruminal hydrogen sulfide concentration, and trace-mineral status of growing beef heifers.

In the Northern Great Plains, cattle may be exposed to water with an elevated sulfate concentration resulting in ruminal hydrogen sulfide (H2S) production and risk of copper deficiency. There are currently few strategies available to help mitigate effects arising from high-sulfate water (HS). The objective of this study was to evaluate the effects of feeding a moderate-forage diet with or without bismuth subsalicylate (BSS; 0.0% vs. 0.4% DM basis) when provided water with a low- (LS; 346 ±â€…13) or HS (4,778 ±â€…263 mg/L) concentration on feed and water intake, ruminal H2S concentration, and liver and serum trace-mineral concentrations. Twenty-four Limousin × Simmental cross beef heifers (221 ±â€…41 kg) were stratified based on initial liver Cu into a completely randomized block design with a 2 × 2 factorial treatment arrangement. Feed and water intake (measured weekly), ruminal H2S concentration (measured on days 42 and 91), liver (measured on days -13 and 91), and serum trace-mineral concentrations (measured on days 1, 28, 56, and 91) were evaluated. Initial liver trace-mineral concentrations were used as a covariate in the statistical model. Water intake tended to be reduced with the inclusion of BSS (P = 0.095) but was not affected by water sulfate (P = 0.40). Water sulfate and BSS did not affect dry matter intake (DMI; P ≥ 0.89). Heifers consuming HS had a ruminal H2S concentration that was 1.58 mg/L more (P < 0.001) than LS. The inclusion of BSS reduced (P = 0.035) ruminal H2S concentration by more than 44% (1.35 vs. 0.75 mg/L). Regardless of the water sulfate concentration, heifers fed BSS had lesser liver Cu concentration (average of 4.08 mg/kg) than heifers not provided BSS, and when not provided BSS, HS had lesser Cu than LS (42.2 vs. 58.3; sulfate × BSS, P = 0.019). The serum concentration of Cu did not differ over time for heifers not provided BSS; whereas, heifers provided BSS had lesser serum Cu concentration on day 91 than on days 28 and 55 (BSS × time, P < 0.001). The liver concentration of selenium was reduced (P < 0.001) with BSS inclusion but the selenium concentration in serum was not affected by sulfate, BSS, or time (P ≥ 0.16). BSS reduced ruminal H2S concentration, but depleted liver Cu and Se. Moreover, sulfate concentration in water did not appear to affect DMI, water intake, or growth, but increased ruminal H2S and reduced liver Cu concentration.

Water containing a high concentration of sulfate increases the risk of hydrogen sulfide production in the rumen and consequently of polioencephalomalacia. In addition, water with a high-sulfate concentration may induce copper deficiency indicated by depleted liver copper concentration. Bismuth subsalicylate (BSS) can bind to sulfides and may reduce the risk of hydrogen sulfide production and therefore may mitigate risks associated with high-sulfate water. In this study, the effects of water sulfate concentrations (346 ±â€…13 vs. 4,778 ±â€…263 mg/L) were tested along with 0.0% vs. 0.4% of dietary BSS. Water intake tended to be reduced with the inclusion of BSS but was not affected by water sulfate. Water sulfate concentration and BSS did not affect dry matter intake (DMI). Heifers consuming high-sulfate water (HS) had a ruminal H2S concentration that was 1.58 mg/L more than low-sulfate water (LS). The inclusion of BSS reduced ruminal H2S concentration by 44% (1.35 vs. 0.75 mg/L). Regardless of the water sulfate concentration, heifers fed BSS had lesser liver Cu concentration than heifers not provided BSS, and when not provided BSS, HS had lesser Cu than LS. BSS reduced ruminal hydrogen sulfide concentration but depleted liver Cu. Sulfate concentration in water did not affect DMI, water intake, or growth, but increased ruminal hydrogen sulfide concentration and reduced liver Cu concentration.

Community Consensus Guidelines to Support FAIR Data Standards in Clinical Research Studies in Primary Mitochondrial Disease.

Primary mitochondrial diseases (PMD) are genetic disorders with extensive clinical and molecular heterogeneity where therapeutic development efforts have faced multiple challenges. Clinical trial design, outcome measure selection, lack of reliable biomarkers, and deficiencies in long-term natural history data sets remain substantial challenges in the increasingly active PMD therapeutic development space. Developing "FAIR" (findable, accessible, interoperable, reusable) data standards to make data sharable and building a more transparent community data sharing paradigm to access clinical research metadata are the first steps to address these challenges. This collaborative community effort describes the current landscape of PMD clinical research data resources available for sharing, obstacles, and opportunities, including ways to incentivize and encourage data sharing among diverse stakeholders. This work highlights the importance of, and challenges to, developing a unified system that enables clinical research structured data sharing and supports harmonized data deposition standards across clinical consortia and research groups. The goal of these efforts is to improve the efficiency and effectiveness of drug development and improve understanding of the natural history of PMD. This initiative aims to maximize the benefit for PMD patients, research, industry, and other stakeholders while acknowledging challenges related to differing needs and international policies on data privacy, security, management, and oversight.

Comparison of constant load exercise intensity for verification of maximal oxygen uptake following a graded exercise test in older adults.

Maximal oxygen uptake (VO2 max) declines with advancing age and is a predictor of morbidity and mortality risk. The purpose here was to assess the utility of constant load tests performed either above or below peak work rate obtained from a graded exercise test for verification of VO2 max in older adults. Twenty-two healthy older adults (9M, 13F, 67 ± 6 years, BMI: 26.3 ± 5.1 kg·m-2 ) participated in the study. Participants were asked to complete two experimental trials in a randomized, counterbalanced cross-over design. Both trials (cycle ergometer) consisted of (1) an identical graded exercise test (ramp) and (2) a constant load test at either 85% (CL85; n = 22) or 110% (CL110; n = 20) of the peak work rate achieved during the associated ramp (performed 10-min post ramp). No significant differences were observed for peak VO2 (L·min-1 ) between CL85 (1.86 ± 0.72; p = 0.679) or CL110 (1.79 ± 0.73; p = 0.200) and the associated ramp (Ramp85, 1.85 ± 0.73; Ramp110, 1.85 ± 0.57). Using the study participant's mean coefficient of variation in peak VO2 between the two identical ramp tests (2.9%) to compare individual differences between constant load tests and the associated ramp revealed 19/22 (86%) of participants achieved a peak VO2 during CL85 that was similar or higher versus the ramp, while only 13/20 (65%) of participants achieved a peak VO2 during CL110 that was similar or higher versus the ramp. These data indicate that if a verification of VO2 max is warranted when testing older adults, a constant load effort at 85% of ramp peak power may be more likely to verify VO2 max as compared to an effort at 110% of ramp peak power.

Evaluation of the depth and duration of anesthesia from heated lidocaine/tetracaine (Synera) patches compared with placebo patches applied to healthy adult volunteers.

BACKGROUND: The heated lidocaine/tetracaine patch (Synera; ZARS Pharma, Inc, Salt Lake City, UT) is among the local topical anesthetic formulations used to prevent procedural pain. This study was conducted to determine the depth and duration of anesthesia provided by the patch and to evaluate safety and tolerability. METHODS: This randomized, double-blind, placebo-controlled, 2-period crossover study was conducted in healthy subjects. Subjects were randomized to receive either the heated lidocaine/tetracaine patch (active patch) in period 1 and placebo patch in period 2 or vice versa. Patches were applied for 30 mins to the volar aspect of the forearm. Pain and sensory depths were measured at baseline and at 30, 60, 90, and 150 mins after patch application. Duration of anesthesia was measured at 40, 70, 110, and 130 mins after patch application by evaluating thermal and mechanical sensation. RESULTS: A total of 25 subjects were enrolled in the study. Twenty-four subjects completed the study. Pain and sensory depths with the active patch were greater than with placebo (P < 0.001) at all postdose time points. Maximum mean pain depth achieved with the active patch was 8.22 mm; anesthesia lasted at least 100 mins after patch removal. Cool and warm sensations and hot pain thresholds were increased compared with placebo (P < 0.001). Light touch and pinprick were detectable by most subjects. CONCLUSIONS: The heated lidocaine/tetracaine patch is well tolerated, and it provides favorable depth and duration of anesthesia without significant sensory loss for superficial venous access and minor dermatological procedures after a 30-min application.

Contribution of a heating element to topical anesthesia patch efficacy prior to vascular access: results from two randomized, double-blind studies.

CONTEXT: Pain associated with superficial procedures, including intravenous (IV) access procedures, should be prevented when possible, especially in children. OBJECTIVES: To evaluate a topical local anesthetic patch containing lidocaine 70 mg/tetracaine 70 mg with a heating element designed to warm the skin and facilitate rapid delivery of local anesthetics into the skin. The pilot study was designed to provide data to inform the design of the definitive study to evaluate the impact of controlled heat on the efficacy of the lidocaine/tetracaine patch (patch) when applied before IV cannulation. METHODS: Subjects in the pilot study were randomized to eight groups that varied by heated vs. unheated patch, 20 vs. 30 minute application, and 16 vs. 18 G catheter. Subjects in the definitive study were randomized in a double-blind manner to receive either the heated or unheated patch, 20 minutes before vascular access, using a 16 G catheter in the antecubital space of the arm. In both studies, the primary efficacy measure was subject-reported pain intensity using a visual analog scale. RESULTS: Pilot study: Subjects who received the heated patch (n=43) vs. the unheated patch (n=37) had lower mean pain intensity scores (14.7 vs. 23.5mm, P=0.04). Pain intensity scores did not differ significantly by application time, but the difference between the 16 and 18 G catheter groups approached statistical significance (22.8 vs. 14.9 mm, P=0.05). Definitive study: Mean pain intensity scores for the heated patch group (n=124) vs. the unheated patch group (n=126) were 14.2 and 20.5mm, respectively (P=0.006). CONCLUSION: Heated patches provided significantly better pain relief compared with unheated patches. All the subjects tolerated the patches well, with few adverse effects.

Instrumented examination of anterior cruciate ligament injuries: minimizing flaws of the manual clinical examination.

The clinical examination is a basic language of orthopaedics; it is how orthopaedic surgeons communicate with one another. However, each surgeon speaks a different dialect that has been influenced by where and with whom that surgeon trained, as well as that person's own experiences. Because of the inherent variability in the magnitude, direction, and rate of force application during the clinical examination, manual arthrometers were developed in an attempt to more consistently quantify the clinical examination. Instrumented manual devices, such as the KT-1000 (MEDmetric, San Diego, CA), were the first to provide objective numbers to surgeons and researchers evaluating anteroposterior (AP) knee joint laxity. Although these devices provide surgeons with feedback related to the amount of force applied, the rate at which the force is applied is uncontrolled, resulting in a lack of reliability similar to that of the clinical examination itself. In addition to potential errors in measuring AP laxity, rotational laxity has proven to be very difficult to quantify. Robotic systems that make use of computer-driven motors to perform laxity testing have recently been developed to control the magnitude, direction, and rate of force application and thus improve the accuracy and reliability of both AP and rotational laxity evaluation. This review discusses the evolution of instrumented clinical knee examination over the past 3 decades and highlights the advantages and disadvantages of the various testing systems, as well as how current and future developments in this area may improve the field of orthopaedics by minimizing the flaws of the manual clinical examination.

Treatment response and tolerability of frovatriptan in patients reporting short- or long-duration migraines at baseline.

OBJECTIVES: Compare migraine duration with frovatriptan (versus baseline) in migraineurs reporting long- (24-72 h) or short-duration (<24 h) migraines at baseline. METHODS: Post hoc analysis of two postmarketing surveillance studies of migraineurs in German primary care clinics using frovatriptan (2.5 mg) to treat a single migraine attack. Using case-report forms, physicians recorded migraine characteristics at baseline (aura, duration, frequency, severity) and with frovatriptan (duration, severity, and recurrence). Patients and physicians rated frovatriptan effectiveness and tolerability versus previous therapy; physicians recorded adverse reactions. The primary analysis was change in migraine duration with frovatriptan versus baseline. RESULTS: At baseline, 44.2% (7178/16 253) and 55.8% (9075/16 253) of patients reported short- and long-duration migraines, respectively; long-duration migraines were more often frequent (> or =3/months; 55.5% [4893/8811] vs. 30.6% [2132/6973]; p < 0.001; 95% CI, 23.5-26.5%), severe (61.7% [5584/9047] vs. 33.9% [2427/7156]; p < 0.001; 95% CI, 26.3-29.3%), and accompanied by aura (46.8% [4199/8977] vs. 31.3% [2215/7088]; p < 0.001; 95% CI, 14.0-17.0%). Mean (SD) onset of frovatriptan effect was <1 h; 72.3% (11 592/16 040) of patients required only one frovatriptan tablet. With frovatriptan, patients were 26.8-fold more likely to experience decreased versus increased headache duration (p < 0.001; 95% CI, 23.5-30.2) and 76.5% of patients reporting long-duration migraines at baseline experienced short-duration migraines. Most patients (87-90%) and physicians (70-75%) rated frovatriptan more effective and tolerable than previous therapies. CONCLUSION: Patients with more severe migraine characteristics at baseline were more likely to have attacks lasting > or =24 h. When using frovatriptan, patients were 26.8-fold more likely to experience decreased versus increased headache duration. Frovatriptan might be a good option for patients with long-duration or recurrent migraine attacks. The post hoc design and analysis of a single migraine attack are possible study limitations.

Safety and tolerability of frovatriptan in the acute treatment of migraine and prevention of menstrual migraine: Results of a new analysis of data from five previously published studies.

BACKGROUND: Triptans are a recommended first-line treatment for moderate to severe migraine. OBJECTIVE: Using clinical trial data, we evaluated the safety and tolerability of frovatriptan as acute treatment (AT) and as short-term preventive (STP) therapy for menstrual migraine (MM). METHODS: Data from 2 Phase III AT trials (AT1: randomized, placebo controlled, 1 attack; AT2: 12-months, noncomparative, open label) and 3 Phase IIIb STP trials in MM (MMP1 and MMP2: randomized, placebo controlled, double blind, 3 perimenstrual periods; MMP3: open label, noncomparative, 12 perimenstrual periods) were analyzed. In AT1, patients treated each attack with frovatriptan 2.5 mg, sumatriptan 100 mg, or placebo. In AT2, they used frovatriptan 2.5 mg. In MMP1 and MMP2, women administered frovatriptan 2.5 mg for 6 days during the perimenstrual period, taking a loading dose of 2 or 4 tablets on day 1, followed by once-daily or BID frovatriptan 2.5 mg, respectively; in MMP3, they used BID frovatriptan 2.5 mg. In AT1, which was previously published in part, group differences in adverse events (AEs) were analyzed using the Fisher exact test, and response rates were compared using logistic regression. Post hoc analyses of sustained pain-free status with no AEs (SNAE) and sustained pain response with no AEs (SPRNAE) were performed using a 2-sample test for equality of proportions without continuity correction. For AT2 and the STP studies, data were summarized using descriptive statistics. Results of individual safety analyses for the STP studies were previously reported; the present report includes new results from a pooled analysis of MMP1 and MMP2 and a new analysis of MMP3 in which AEs were coded using Medical Dictionary for Regulatory Activities version 8.0. RESULTS: AT1 included 1206 patients in the safety group; AT2 included 496. In the STP studies, safety data were collected for 1487 women. In AT1 and AT2, 85.6% and 88.3%, respectively, of enrolled patients were women. Overall, AEs were generally mild to moderate (AT studies: 82.3%-90.0%; STP studies: 78.9%89.5%). In AT1, 27.3% (131/480) of frovatriptan patients, 33.4% (161/482) of sumatriptan patients, and 14.8% (36/244) of placebo patients experienced an AE considered possibly or probably related to treatment (P < 0.001 for either drug vs placebo).There were no significant differences between frovatriptan and sumatriptan in SNAE at 4 to 24 hours or in SPRNAE at 2 to 24 hours or at 4 to 24 hours. In randomized, controlled STP trials for MM, AEs were reported by 57.8% (166/287, BID) and 63.4% (210/331, once daily) of frovatriptan users versus 62.8% (216/344) of placebo recipients. There were no consistent differences in AEs reported by patients with potential cardiovascular risk or in AEs related to the use of estrogencontaining contraceptives (ECCs). CONCLUSIONS: In randomized controlled trials and 12-month open-label studies, frovatriptan was well tolerated in these women during AT and STP therapy for MM. Subgroup analyses provide preliminary evidence of tolerability in women using ECCs and in women with comorbidities that do not contraindicate triptan use but may be suggestive of cardiovascular risk.

Characteristics of menstrual vs nonmenstrual migraine: a post hoc, within-woman analysis of the usual-care phase of a nonrandomized menstrual migraine clinical trial.

OBJECTIVE: To compare, using a within-woman analysis, the severity, duration, and relapse of menstrual vs nonmenstrual episodes of migraine during treatment with usual migraine therapy. BACKGROUND: Studies comparing the clinical characteristics of menstrual and nonmenstrual migraine attacks have yielded conflicting results, contributing to disagreement regarding whether menstrual migraine attacks are clinically more problematic than nonmenstrual migraine attacks. METHODS: Post hoc within-woman analysis of the usual-care phase (month 1) of a 2-month, multicenter, prospective, open-label study at 21 US medical practices (predominantly primary care). Participants were women > or =18 years of age with regular predictable menstrual cycles (28 +/- 4 days) who self-reported a > or =1-year history of migraine attacks occurring between days -2 and +3 (menses onset = day +1) and > or =8 such attacks within the previous 12 cycles. Migraine treatment episodes were categorized as menstrual (occurring on days -2 to +3 of menses) or nonmenstrual (occurring on days +4 to -3 of menses). Pain severity, functional impairment, duration, relapse in 24 hours, and use of rescue medication were compared. Sources of variability (within- or between-patient) were determined using mathematical modeling. The http://www.clinicaltrial.gov code for trial is NCT00904098. RESULTS: Women (n = 153; intent to treat) reported 212 menstrual (59.2%) and 146 nonmenstrual (40.8%) migraine treatment episodes. Compared with nonmenstrual treatment episodes, menstrual episodes were more likely to cause impairment (unadjusted odds ratio, 1.65, 95% CI, 1.05-2.60; P = .03), were longer (unadjusted hazard ratio 1.68; 95% CI, 1.31-2.16; P < .001), and were more likely to relapse within 24 hours (unadjusted odds ratio, 2.66; 95% CI, 1.25-5.68; P = .01). Within-patient effects accounted for only 18-33% of the total variance in these outcomes. CONCLUSIONS: Post hoc, within-woman analysis of migraine treatment episodes categorized based on International Headache Society criteria showed that menstrual treatment episodes were more impairing, longer lasting, and more likely to relapse than nonmenstrual treatment episodes in this selected population of women with frequent menstrual migraine. The current analysis indicates that most of the variability in these outcomes is due to differences between headache types and not within-patient differences for a given type of headache, suggesting that menstrual episodes are potentially treatable. These findings underscore the differences between menstrual and nonmenstrual episodes of migraine and the need to offer effective migraine treatment to women.

Scheduled short-term prevention with frovatriptan for migraine occurring exclusively in association with menstruation.

OBJECTIVE: This post hoc subgroup analysis evaluated scheduled short-term preventive frovatriptan therapy for women with migraine occurring exclusively in association with menstruation (occurring day -2 to +3; day 1 = menses start, no migraines outside this window). BACKGROUND: A previously published randomized, double-blind, placebo-controlled 3-way crossover trial assessed the efficacy and safety of a scheduled 6-day preventive regimen with frovatriptan for the treatment of menstrual migraine; the study population included women experiencing both menstrual and non-menstrual migraine and women experiencing only menstrual migraine. METHODS: Women received each treatment (placebo, frovatriptan 2.5 mg once daily, and frovatriptan 2.5 mg twice daily) once over 3 perimenstrual periods in randomized sequence. For this subset analysis, screening questions were used to identify women with migraine occurring exclusively in association with menstruation. Efficacy was evaluated by occurrence and severity of migraine, functional impairment, and rescue medication use. Adverse events and tolerability were also assessed. RESULTS: Among 179 patients, the mean age (SD) was 37.3 (7.7) years and mean menstrual migraine history was 10.6 (8.7) years. Significantly fewer women experienced menstrual migraine during treatment with frovatriptan twice daily (37.7%, P < .001) or once daily (51.3%, P = .002) than during treatment with placebo (67.1%); a significant dose response was noted (P = .01, twice daily vs once daily). Significant treatment differences were also found for several secondary endpoints, but the data from this post hoc analysis must be interpreted with caution. Frovatriptan was well tolerated and most adverse events were mild or moderate and similar to those reported with the acute treatment of migraine with frovatriptan; the most common adverse events were nausea, dizziness, and headache. CONCLUSIONS: Scheduled short-term preventive frovatriptan therapy effectively reduced the occurrence of menstrual migraine in women with attacks occurring exclusively in association with menstruation.