Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients.

Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.

Diet Supplementation with Soy Protein Isolate, but Not the Isoflavone Genistein, Protects Against Alcohol-Induced Tumor Progression in DEN-Treated Male Mice.

Diethylnitrosamine-treated male mice were assigned to 4 groups: a casein-based 35% high fat ethanol liquid diet (EtOH), an EtOH diet made with soy protein isolate protein (EtOH/SOY), an EtOH liquid diet supplemented with genistein (EtOH/GEN) and a chow group. EtOH feeding, final concentration 5% (v/v), continued for 16 wks. EtOH increased incidence and multiplicity of basophilic lesions and adenomas compared to the chow group, (p < 0.05). The EtOH/SOY group had reduced adenoma progression when compared to the EtOH and EtOH/GEN group, (p < 0.05). Genistein supplementation had no protective effect. Soy feeding significantly reduced serum ALT concentrations (p < 0.05), decreased hepatic TNFα and CD-14 expression and decreased nuclear accumulation of NFκB protein in EtOH/SOY-treated mice compared to the EtOH group (p < 0.05). With respect to ceramides, high resolution MALDI-FTICR Imaging mass spectrometry revealed changes in the accumulation of long acyl chain ceramide species, in particular C18, in the EtOH group when compared to the EtOH/SOY group. Additionally, expression of acid ceramidase and sphingosine kinase 1 which degrade ceramide into sphingosine and convert sphingosine to sphingosine-1-phosphate (S1P) respectively and expression of S1P receptors S1PR2 and S1PR3 were all upregulated by EtOH and suppressed in the EtOH/SOY group, p < 0.05. EtOH feeding also increased hepatocyte proliferation and mRNA expression of ß-catenin targets, including cyclin D1, MMP7 and glutamine synthase, which were reduced in the EtOH/SOY group, p < 0.05. These findings suggest that soy prevents tumorigenesis by reducing inflammation and by reducing hepatocyte proliferation through inhibition of EtOH-mediated ß-catenin signaling. These mechanisms may involve blockade of sphingolipid signaling.

Gas Phase Ion Chemistry to Determine Isoaspartate in a Peptide Backbone.

Proof of concept evidence is presented for a new method for the determination of isoaspartate, an important post-translational modification. Chemical derivatization is performed using common reagents for the modification of carboxylic acids and shown to yield suitable diagnostic information with regard to isomerization at the aspartate residue. The diagnostic gas phase chemistry is probed by collision-induced dissociation mass spectrometry, on the timescale of the MS experiment and semi-quantitative calibration of the percentage of isoaspartate in a peptide sample is demonstrated. Graphical Abstract ᅟ.

Continuous in-home monitoring of essential tremor.

BACKGROUND: Essential tremor (ET) is typically measured in the clinic with subjective tremor rating scales which require the presence of a clinician for scoring and are not appropriate for measuring severity throughout the day. Motion sensors can accurately rate tremor severity during a set of predefined tasks in a laboratory. METHODS: We evaluated the ability of motion sensors to quantify tremor during unconstrained activities at home. 20 ET subjects wore a wireless sensor continuously for up to 10 h daily on two days and completed hourly standardized tremor assessments involving pre-defined tasks. Mathematical models were used to predict tremor rating scores from the sensor data. RESULTS: At home tremor scores from hourly standardized assessments correlated with at home tremor scores estimated during unconstrained activities immediately following the standardized assessments. The hourly standardized assessments did not significantly fluctuate throughout the day, while fluctuations in the continuous assessments tended to follow changes in voluntary activity level. Both types of tremor ratings (standardized and continuous) showed high day-to-day test-retest reliability with intraclass correlation coefficients ranging from 0.67 to 0.90 for continuous ratings and 0.77 to 0.95 for standardized ratings. CONCLUSIONS: Results demonstrate the feasibility of continuous monitoring of tremor severity at home, which should provide clinicians with a measure of the temporal pattern of tremor in the context of daily life and serve as a useful tool for the evaluation of novel anti-tremor medications in clinical trials.

Psychosocial differences in high risk versus low risk acute low-back pain patients.

The current study built upon previous research that predicted with 90.7% accuracy which patients presenting with acute low-back pain go on to develop chronic disability problems. Fifty-seven patients were classified as high risk (HR) or low risk (LR) according to a predictive algorithm, and were evaluated with a variety of psychosocial measures. Overall, HR patients had more Axis I pathology than LR patients, and used poorer coping styles. Logistic regression analyses identified variables that differentiated, with 80% accuracy, between the HR and LR patients. The results highlight the importance of identifying patients who are at risk for developing chronic pain following acute injury so that prophylactic intervention can be offered before chronic pain disability status becomes entrenched.

Dental factors in the genesis of squamous cell carcinoma of the oral cavity.

This study investigated the role of dental factors in the genesis of squamous cell carcinomas of the oral cavity. 99 newly diagnosed patients with advanced head and neck cancer were evaluated for potential demographic, dental and prosthetic risk factors. Patients with extra-oral malignancies were used as controls in the analysis of dental factors in patients with intra-oral cancers. We performed multiple comparisons of these factors against the primary tumour sites. An analysis of dental and prosthetic factors and patients with intra-oral versus extra-oral tumours revealed no significant differences. However, all 28 intra-oral malignancies arose in areas in contact with teeth and/or appliances. For example, all 10 oral tongue lesions arose on the lateral borders and all six floor of (drop) mouth primary tumours developed at the flange extension of a lower denture. Patients with partial or full dentures had significantly lower node (N) scores than patients without a prosthesis. Although this paper suggests a relationship between dental factors and the genesis of oral squamous cell malignancies, a larger prospective study would be required to achieve definitive data. Patients at risk should be followed carefully for the development of chronic irritation from teeth and appliances.

Reliability of a modified medication appropriateness index in ambulatory older persons.

OBJECTIVE: To evaluate the reliability of a medication appropriateness index (MAI) modified for elderly outpatients in a non-Veterans Affairs setting. DESIGN: Reliability study. SETTING: General community. PARTICIPANTS: Ten community-dwelling elderly (> 65 y) taking five or more regularly scheduled medications and participating in a university-based health service intervention study. MAIN OUTCOME MEASURES: Interrater reliability of MAI ratings of 65 medications made by two clinical pharmacists for individual items and for an overall summed score was calculated by use of kappa statistics and intraclass correlation coefficient. RESULTS: The interrater agreement for each of the individual MAI items was high for both appropriate and inappropriate ratings and ranged from 80% to 100% (overall kappa = 0.64). Overall agreement for the summed score was good (intraclass correlation = 0.80). CONCLUSIONS: The modified MAI is a reliable instrument for evaluation of medication appropriateness in a non-Veterans Affairs, ambulatory, elderly population and may provide pharmacists with a practical and standard method to evaluate patients' drug regimens and identify some potential drug-related problems.

Motivational factors in the choice of postdoctoral general dentistry programs.

This study explored the importance of various personal and professional factors that may influence choices concerning postdoctoral training in general dentistry. We sent an eighty-one-question survey to all individuals (N = 1,995) who were registered to participate in the Postdoctoral Dental Matching Program (MATCH) and analyzed 599 returned surveys from those applying to GPR and/or AEGD programs. Approximately twenty questions addressed each of four time periods in the application process. Over half of respondents felt that learning more medicine, increasing their speed with dental procedures, gaining confidence in clinical skills, and treating compromised patients were very important. Over one-third of respondents felt that program location, salary and benefits, program philosophy and faculty, and nondental training experiences were very important. Females felt that thirty-five items were more important than did their male counterparts, whereas males indicated that two items were more important. While there were some differences between applicants to AEGD versus GPR programs, there were far more areas where the applicants to each of these programs shared common concerns. The data suggest that the majority of individuals who consider postgraduate general dentistry programs perceive a lack of experience at the predoctoral level relating to clinical dentistry in general and specifically to their understanding of medical principles and managing compromised patients.

Breastfeeding, dehydration, and shorter maternity stays.

Over a five-month period eight breastfed infants required readmission to Wesley Long Community Hospital in Greensboro, North Carolina, within 48 hours of discharge from the newborn nursery. The primary diagnoses upon readmission included hyperbilirubinemia and suspected sepsis. At discharge from the intensive care nursery, mild dehydration secondary to inadequate breastfeeding was deemed a significant factor in precipitating the need for readmission. This increase in readmissions represented a significant change from the past year. An intensive review of each initial hospital stay was conducted to attempt to identify causative factors and to develop a profile of infants who might be at risk for readmission in the future.

Characteristics predicting incorrect metered-dose inhaler technique in older subjects.

OBJECTIVE: To determine whether cognitive status, hand strength, and demographic variables are predictive of correct use of metered-dose inhalers by older subjects. METHODS: Clinic patients (n = 29) and healthy volunteers (n = 42) older than 50 years with no previous or limited metered-dose inhaler use were enrolled. After cognitive (Mini-Mental State Examination) and hand strength assessments, subjects received extensive instruction in proper metered-dose inhaler technique. Technique was independently assessed by two evaluators immediately after instruction and 1 week later. Correct technique was defined as (1) activating the canister in the first half of inhalation, (2) continuing to inhale slowly and deeply, and (3) holding breath at full inspiration (5 seconds). Data for the two subject groups were pooled for analyses. RESULTS: The mean age of the subjects was 69.7 years. Forty subjects (56%) demonstrated correct metered-dose inhaler technique at 1 week. Logistic regression showed that hand strength measurement (odds ratio, 0.68; 95% confidence interval, 0.55 to 0.84), Mini-Mental State Examination score less than 24 (odds ratio, 3.66; 95% confidence interval, 1.07 to 12.4), and male gender (odds ratio, 5.01; 95% confidence interval, 1.07 to 23.5) were significant predictors of incorrect inhaler use. Correct use of the metered-dose inhaler was unrelated to age, education, or subject status. CONCLUSIONS: Clinicians should consider cognitive status and hand strength when metered-dose inhaler therapy is initiated for an older adult. Patients with cognitive impairment and hand strength deficits may require more extensive training, frequent follow-up, or alternative dosage forms.

P-wave duration in a clinically normal hound population.

Electrocardiogram (ECG) analysis is a common noninvasive technique used for diagnosis of cardiac disease in the clinical and research branches of veterinary medicine. Accurate analysis of P-wave duration, amplitude, and morphology is crucial to identification of morphologic and functional changes of the atria. The published accepted maximal normal value for P-wave duration in the dog is < or = 40 milliseconds. We looked at P-wave duration in ECG obtained as part of routine quarantine health screening over a period of 1 year in 364 clinically normal hounds weighing 13 to 35 kg. The dogs were neither anesthetized nor sedated and were placed in standard position. P-wave duration was classically determined from the lead-II recording. Mean P-wave duration for all dogs (44.9 +/- 6.1 milliseconds) was greater than published accepted normal values for the dog. There was a significant difference in mean P-wave duration by body weight (P < 0.001); dogs weighing > or = 20 kg had longer mean P-wave durations than dogs weighing < 20 kg (45.3 and 41.6 milliseconds respectively). There were also significant differences in mean P-wave duration by sex (P < 0.01), with a greater mean duration for females (45.4 milliseconds) than for males (43.8 milliseconds). All other ECG parameters were within published accepted normal values. A P-wave of prolonged duration leads to a diagnosis of abnormalities in cardiac morphology and/or function. Published accepted normal values for P-wave duration, at least for a clinically normal hound population, appear to be shorter than the true normal values. An error in published accepted normal standards may lead to overdiagnosis of cardiac abnormalities, as well as to erroneous results in cardiovascular studies. Therefore we recommend that the standard for P-wave duration be increased above the currently accepted standard of < or = 40 milliseconds.

Enforcement of drunken driving laws in cases involving injured intoxicated drivers.

STUDY OBJECTIVE: To determine the frequency of driving while impaired (DWI) charges among alcohol-intoxicated drivers injured in motor vehicle crashes (MVCs) and any differences in the group of those charged compared with those not charged. METHODS: We performed a retrospective analysis of linked data from medical and judicial sources. Our setting was an urban emergency department of a trauma center serving a population of 1 million. We studied consecutive drivers injured in MVCs over a period of 15 months who had measured serum ethanol (BAC) levels of 100 mg/dL or higher. BAC, Trauma Score (TS), demographics, and crash data were linked to court records of charges, outcome, and prior convictions. The group of individuals who were charged with DWI were compared with those who were not charged. RESULTS: One hundred eighty-seven patients were studied; 53 (28%) were charged with DWI, and 32 (17% of total) were convicted. Two (7%) of 29 patients with severe injuries, 9 (28%) of 32 with moderate injuries, and 42 (33%) of 126 with nonsevere injuries were charged (P = .004). Eighteen (16%) of 112 patients with no prior convictions were charged; 20 (56%) of 36 patients with one, 11 (52%) of 21 with two, 3 (25%) of 12 with three, and 0 of 5 with four or more prior DWI convictions were charged (P < .001). There were no significant differences in BAC, demographics, or other measures between the two groups. CONCLUSION: Alcohol-impaired drivers who require ED treatment for injuries sustained in an MVC are infrequently charged with DWI. The likelihood of a DWI charge diminishes with increasing severity of injury. Repeat offenders are charged more often, but the frequency of charges does not increase with increasing number of prior DWI convictions.

Assessment of interrater and intrarater reliability in the evaluation of metered dose inhaler technique.

STUDY OBJECTIVE: To determine if a training session using videotaped metered dose inhaler (MDI) performances can result in high interrater and intrarater reliability of five evaluators assessing MDI technique. DESIGN: Five evaluators (three pharmacists, two pulmonary fellows) were trained to evaluate MDI technique during a 2-h training session. The training session consisted of verbal instruction and practical experience in evaluating MDI technique using video-taped MDI performances of six nonstudy subjects. After the training session, the evaluators independently observed the same videotaped MDI demonstrations of 14 subjects on two occasions separated by a 7- to 10-day interval. Interrater and intrarater reliability was determined for individual steps by calculating percent agreement and intraclass correlation (ICC) coefficient. RESULTS: Interrater. The interrater reliability for individual steps ranged from 29 to 86 percent (ICC coefficient = 0.13 to 0.81). Steps in which evaluators were in agreement for less than 9 of the 14 subjects were shaking the inhaler before inhalation, exhaling, continuing to inhale slowly, and adequate breath hold. Intrarater: The overall percent agreement by step ranged from 74 to 97 percent. Exhaling to functional residual volume (76 percent) and continuing to inhale slowly and deeply (74 percent) had the lowest overall agreement between the first and second observation day. The consistency of evaluating a step between the two observation days varied considerably depending on the step and evaluator. CONCLUSIONS: High interrater and intrarater reliability in MDI evaluation is difficult to obtain. Clinicians and researchers involved in MDI evaluation and education should be trained to achieve consistency. A single training session using videotaped MDI demonstrations was not adequate in achieving consistency among evaluators. To improve accuracy of research results, researchers should include at least two evaluators to assess MDI technique or take other measures to show and report reliability.

Venous duplex scanning in the diagnosis and treatment of progressive superficial thrombophlebitis.

Venous duplex scanning, employing both B-Mode imaging and Doppler waveform analysis, is a valuable noninvasive technique for the evaluation of venous disorders of the lower extremities. During the past three years, 442 venous duplex scans were performed in our laboratory, evaluating both the deep and superficial venous systems. Sixty-four scans revealed deep venous thrombosis; twenty studies revealed superficial thrombophlebitis. A subgroup of six studies revealed progressive thrombophlebitis approaching or involving the deep venous system. Three of these six studies documented progression of superficial thrombophlebitis extending into the deep venous system, producing limited deep venous thrombosis. All six patients were treated with venous excision and local venous thrombectomy. None of the patients developed deep venous thrombosis on follow-up venous duplex scans. We conclude that venous duplex scanning is a valuable noninvasive method in the detection of progressive superficial thrombophlebitis. Therefore, prompt therapy may prevent the development of deep venous thrombosis and its sequelae. Additionally, venous duplex scanning provides a method for noninvasive follow-up of the results of therapy.

Reoperative carotid surgery.

Fourteen patients underwent carotid reoperation for symptomatic recurrent carotid stenosis after previous ipsilateral carotid endarterectomy. Eight of these patients presented with focal transient ischemic attacks, two with strokes, and four with vertebrobasilar insufficiency. Recurrent symptoms in eight patients were similar to those prompting the initial carotid endarterectomy. Symptoms recurred early after previous carotid endarterectomy in 2 patients and late in 12 patients. Eleven patients underwent repeat endarterectomy and carotid patch angioplasty, two patients underwent patch angioplasty alone, and one patient underwent carotid artery replacement with a vein graft. Persistent or recurrent focal symptoms referable to the reoperated carotid artery were not present during follow-up (mean 27.4 months, range 4 to 79 months). Vertebrobasilar symptoms were relieved by carotid reoperation in each patient. Although the natural history of asymptomatic postoperative carotid restenosis is unknown, reluctance to reoperate on symptomatic patients is unwarranted, since carotid reoperation can be performed safely with the expectation that recurrent focal and nonfocal vertebrobasilar symptoms will be relieved.

Cooperative care. The time has come.

What happens when patients decide when to take their medications, when to eat, what to wear, and what family member will stay with them? These authors state the result of these patient self-care activities are reduced cost, and more satisfied patients and staff.