Urine assay for tenofovir to monitor adherence in real time to tenofovir disoproxil fumarate/emtricitabine as pre-exposure prophylaxis.

OBJECTIVES: Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is approved for pre-exposure prophylaxis (PrEP) against HIV infection. Adherence is critical for the success of PrEP, but current adherence measurements are inadequate for real-time adherence monitoring. We developed and validated a urine assay to measure tenofovir (TFV) to objectively monitor adherence to PrEP. METHODS: We developed a urine assay using high-performance liquid chromatography coupled to tandem mass spectrometry with high sensitivity/specificity for TFV that allowed us to determine TFV concentrations in log10 categories between 0 and 10 000 ng/mL. We validated the assay in three cohorts: (1) HIV-positive subjects with undetectable viral loads on a TDF/FTC-based regimen, (2) healthy HIV-negative subjects who received a single dose of TDF/FTC, and (3) HIV-negative subjects receiving daily TDF/FTC as PrEP for 24 weeks. RESULTS: The urine assay detected TFV with greater sensitivity than plasma-based measures and with a window of measurements within 7 days of the last TDF/FTC dose. Based on the urine log-linear clearance after the last dose and its concordance with all detectable plasma levels, a urine TFV concentration > 1000 ng/mL was identified as highly predictive of the presence of TFV in plasma at > 10 ng/mL. The urine assay was able to distinguish high and low adherence patterns within the last 48 h (> 1000 ng/mL versus 10-1000 ng/mL), as well as nonadherence (< 10 ng/mL) extended over at least 1 week prior to measurement. CONCLUSIONS: We provide proof of concept that a semiquantitative urine assay measuring levels of TFV could be further developed into a point-of-care test and be a useful tool to monitor adherence to PrEP.

Comprehensive genetic testing with ethnic-specific filtering by allele frequency in a Japanese hearing-loss population.

Recent advances in targeted genomic enrichment with massively parallel sequencing (TGE+MPS) have made comprehensive genetic testing for non-syndromic hearing loss (NSHL) possible. After excluding NSHL subjects with causative mutations in GJB2 and the MT-RNR1 (1555A>G) variant by Sanger sequencing, we completed TGE+MPS on 194 probands with presumed NSHL identified across Japan. We used both publicly available minor allele frequency (MAF) datasets and ethnic-specific MAF filtering against an in-house database of 200 normal-hearing Japanese controls. Ethnic-specific MAF filtering allowed us to re-categorize as common 203 variants otherwise annotated as rare or novel in non-Japanese ethnicities. This step minimizes false-positive results and improves the annotation of identified variants. Causative variants were identified in 27% of probands with solve rates of 35%, 35% and 19% for dominant, recessive and sporadic NSHL, respectively. Mutations in MYO15A and CDH23 follow GJB2 as the frequent causes of recessive NSHL; copy number variations in STRC are a major cause of mild-to-moderate NSHL. Ethnic-specific filtering by allele frequency is essential to optimize the interpretation of genetic data.

Spontaneous rupture of the right aortic sinus resulting in a sterile aorto-atrial fistula in a pet rabbit (Oryctolagus cuniculus).

Aortocardiac fistula is a broad term used to describe defects between the aorta and other cardiac chambers that can occur in humans and animals. A 1.5-year-old, 1.7 kg, male castrated Holland lop rabbit (Oryctolagus cuniculus) was presented for a two-week history of a heart murmur with corresponding cardiomegaly on radiographs. Physical examination confirmed a grade-V/VI continuous heart murmur on the right sternal border with a regular rhythm and a gallop sound. Echocardiography revealed an aortic-to-right-atrial fistula causing severe left-sided volume overload. Based on the echocardiographic findings, rupture of the right aortic sinus was suspected. Due to the poor prognosis, euthanasia was elected. On necropsy, a fistula was found connecting the right aortic sinus with the right atrium, without evidence of an inflammatory response nor evidence of an infectious etiology. The sudden onset of a heart murmur supported acquired fistulation from a ruptured aortic sinus (also known as the sinus of Valsalva), though a congenital malformation could not be completely excluded.

Effects of exercise on S-IGA and URS in postmenopausal women.

32 postmenopausal women were randomized to a 16-week home-based walking program or control group. Before and after the intervention, each subject completed a graded maximal treadmill test to establish VO(2)max and resting saliva was collected to determine levels of salivary immunoglobulin A. The 16-week walking program resulted in an increase in VO(2)max (+10.4%; p<0.01). Repeated measures ANOVA revealed a marked increase in the resting secretion rate of salivary immunoglobulin A (+37.4%; p<0.05) in the exercise group following training. Independent of study group, both before and after the intervention, the secretion rate of salivary immunoglobulin A ( - 32.3%) and saliva flow rate (- 29.3%) were reduced following acute maximal exercise (p<0.05). Weekly upper respiratory symptomatology logs revealed that the number of incidences of upper respiratory symptoms throughout the intervention period were the same and the duration per incidence (control: 5.3±1.5 days; exercise: 6.3±2.2 days) were similar between study groups. These findings in postmenopausal women support that the secretion rate of salivary immunoglobulin A and saliva flow rate are reduced immediately following maximal exercise. Moreover, a 16-week moderate intense walking program can increase the secretion of salivary immunoglobulin A without affecting upper respiratory symptomatology.

Cerebral subcortical small vessel disease and its relation to cognition in elderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort.

BACKGROUND: Subcortical small vessel disease (SVD) is known to contribute to vascular cognitive impairment and vascular dementia, but understanding about the extent of its influence is limited because there is a lack of consensus about how this pathology should be assessed. METHODS: In this study we have made use of a simple, novel, image-matching scoring system to assess the extent of SVD in a group of 70 cases from the prospectively assessed Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. These cases were found at autopsy to have cerebrovascular disease and no other pathology except Braak stage 4 or less tau pathology, and insufficient amyloid plaque pathology to meet Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria for the diagnosis of Alzheimer's disease. Pathology scores for SVD were correlated with cognitive scores [Mini-Mental State Examination (MMSE) and cognitive section of the Cambridge Examination for Mental Disorders in the Elderly (CAMDEX) (CAMCOG)] at the last clinical assessment before death. RESULTS: The severity of SVD pathology was inversely related to cognitive score before death (P < 0.008 for MMSE and P < 0.024 for CAMCOG). Thirty-one per cent and 33% of cases were rated as demented by MMSE or CAMCOG respectively. The degree of dementia was generally mild. Age did not influence severity of SVD. CONCLUSIONS: An image-based scoring system for SVD in a group of 70 elderly subjects enabled the severity of SVD pathology to be assessed with results that showed a significant correlation between SVD pathology severity and cognitive impairment.

Left atrial dissection after left ventricular aneurysm repair.

Left atrial (LA) dissection is an uncommon entity that occurs most often after mitral valve surgery. We present a case of a 52-year-old man who developed an LA dissection after repair of a postinfarction left ventricular (LV) aneurysm. Transesophageal echocardiography was used to establish the diagnosis of an LA dissection that almost completely occluded the LA, limiting LV filling and causing hemodynamic instability.

Transcatheter closure of aneurysmal perimembranous ventricular septal defect with the canine duct occluder in two dogs.

Congenital membranous ventricular septal aneurysm has been reported in dogs and can be associated with a perimembranous ventricular septal defect (VSD). The windsock-like ventricular septal aneurysm is formed by tissue of the membranous ventricular septum and portions of the septal leaflet of the tricuspid valve. We report two dogs that underwent transcatheter closure of perimembranous VSD associated with membranous ventricular septal aneurysm using a commercial device marketed for transcatheter closure of patent ductus arteriosus, the canine duct occluder. Partial closure was achieved in the first dog with reduction in left heart dimensions documented on echocardiography both at one day and nine months after procedure. In the second dog, three-dimensional transesophageal echocardiography, cardiac computed tomography, and a three-dimensionally printed whole heart model were used to evaluate feasibility for transcatheter device closure. Complete closure of the VSD was subsequently achieved. Both cases had good short- to medium-term outcomes, no perioperative complications were observed, and both dogs are apparently healthy and receiving no cardiac medications at 34 months and 17 months after procedure. Transcatheter attenuation of perimembranous VSD with membranous ventricular septal aneurysm is clinically feasible using the canine duct occluder, and multimodal cardiac imaging allows accurate assessment and planning prior to transcatheter intervention for structural heart disease in dogs.

A multicenter prospective evaluation of owner medication adherence for feline cardiovascular disease in the referral setting.

OBJECTIVE: The aim of this paper is to evaluate owners' chronic medication adherence for management of feline cardiovascular disease in the small animal referral setting. ANIMALS, MATERIALS AND METHODS: A questionnaire-based study of owners at five multispecialty, small animal referral centers was conducted. Owners completed a written survey evaluating demographics, degree of medication adherence, and difficulties encountered for medication adherence. Owners were free to decline participation in the study. RESULTS: Fifty-four questionnaires were available for review. The most common diagnosis was hypertrophic cardiomyopathy (n = 31, 57.4%). Clopidogrel was the most cited medication that was difficult to administer consistently (n = 13, 24.0%) although twenty owners (37.0%) reported no difficulty consistently administering medications. "Taste of medication" (n = 14, 25.9%) was the most reported reason for difficulty medicating their cat, and most owners (n = 36, 66.7%) stated twice daily was the highest frequency of heart medications they feel they can consistently administer. Fifty owners (92.6%) met the criteria for medication adherence. CONCLUSIONS: Chronic medication adherence in this study population was high. Clopidogrel was the most difficult medication to consistently administer, and twice a day dosing was the highest frequency of medication administration most owners could achieve. Cardiologists should be aware of these factors when determining optimal treatment protocols for the management of cardiovascular disease in cats.

Stochastic Resonance Reduces Sway and Gait Variability in Individuals With Unilateral Transtibial Amputation: A Pilot Study.

Sub-threshold (imperceptible) vibration, applied to parts of the body, impacts how people move and perceive our world. Could this idea help someone who has lost part of their limb? Sub-threshold vibration was applied to the thigh of the affected limb of 20 people with unilateral transtibial amputation. Vibration conditions tested included two noise structures: pink and white. Center of pressure (COP) excursion (range and root-mean-square displacements) during quiet standing, and speed and spatial stride measures (mean and standard deviations of step length and width) during walking were assessed. Pink noise vibration decreased COP displacements in standing, and white noise vibration decreased sound limb step length standard deviation in walking. Sub-threshold vibration positively impacted aspects of both posture and gait; however, different noise structures had different effects. The current study represents foundational work in understanding the potential benefits of incorporating stochastic resonance as an intervention for individuals with amputation.

Impact of advanced detector technology and iterative reconstruction on low-dose quantitative assessment of lung computed tomography density in a biological lung model.

PURPOSE: Quantitative computed tomography (QCT)-derived measures of lung density are valued methods for objectively characterizing lung parenchymal and peripheral airways disease and are being used in a growing number of lung disease focused trials. Detector and reconstruction improvements in CT technology have allowed for significant radiation dose reduction in image acquisition with comparable qualitative image quality. We report the impact of detector type and reconstruction type on QCT lung density measures in relation to decreasing dose indices. METHODS: Two sets of studies were completed in an in vivo pig model with a SOMATOM Definition Flash CT system: (a) prior to system upgrade with conventional detectors (UFC) and filtered back projection (FBP), and (b) post system upgrade with integrated electronic detectors (STELLAR) and iterative reconstruction (SAFIRE). CT data were acquired across estimated CT volume dose indices (CTDIvol ) ranging from 0.75 to 15 mGy at both inspiratory and expiratory breath holds. Semiautomated lung segmentations allowed calculation of histogram median, kurtosis, and 15th percentile. Percentage of voxels below -910 HU and -950 HU (inspiratory), and -856 HU (expiratory) were also examined. The changes in these QCT metrics from dose reduction (15 mGy down to 0.75 mGy) were calculated relative to paired reference values (15 mGy). Results were compared based on detector and reconstruction type. RESULTS: In this study, STELLAR detectors improved concordance with 15 mGy values down to 3 mGy for inspiratory scans and 6 mGy for expiratory scans. The addition of SAFIRE reconstruction in all acquired measurements resulted in minimal deviation from reference values at 0.75 mGy. CONCLUSION: The use of STELLAR integrated electronic detectors and SAFIRE iterative reconstruction may allow for comparable lung density measures with CT dose indices down to 0.75 mGy.

Echocardiographic Assessment of Right Ventricular Size and Function in Cats With Hypertrophic Cardiomyopathy.

BACKGROUND: Studies evaluating right ventricular (RV) structural and functional abnormalities in feline hypertrophic cardiomyopathy (HCM) are limited. HYPOTHESIS: Right ventricular structural and functional abnormalities are present in cats with HCM and are associated with clinical severity. ANIMALS: Eighty-one client-owned cats. METHODS: Retrospective 2-dimensional (2D) echocardiographic study. Right atrial diameter (RAD), RV free wall thickness (RVFWd), RV internal dimension (RVIDd), RV fractional area change (FAC), and tricuspid annular plane systolic excursion (TAPSE) were measured in control cats (n = 26), cats with subclinical HCM (subclinical HCM; n = 31), and cats with HCM and congestive heart failure (HCM + CHF; n = 24). RESULTS: Right heart size (RAD, RVFWd, and RVIDd) and RV function (FAC and TAPSE) significantly (all P < .05) increased and decreased, respectively, in the HCM + CHF group compared with controls. In the subclinical HCM group, only RVFWd was significantly (P < .05) higher than in controls. Compared with reference intervals derived from controls, 29% of cats with HCM had increased RVFWd. Increased left ventricular free wall thickness, increased RVIDd and decreased TAPSE independently correlated with increased left atrial size. Cats with HCM and pleural effusion were significantly more likely to have increased RVFWd and had increased RAD and decreased TAPSE compared with cats without pleural effusion. CONCLUSIONS AND CLINICAL IMPORTANCE: Right ventricular remodeling and dysfunction occur in some cats with HCM and may be associated with clinical severity. Our results support involvement of RV in the pathophysiology of HCM in some cats and support echocardiographic assessment of the RV in cats with HCM.

Outpatient high-dose chemotherapy with autologous stem-cell rescue for hematologic and nonhematologic malignancies.

PURPOSE: A prospective study to determine the feasibility of high-dose chemotherapy (HDC) and autologous stem-cell rescue (ASCR) in the outpatient setting. METHODS: One hundred thirteen consecutive patients underwent 165 cycles of HDC/ASCR for a variety of malignancies. HDC regimens were disease-specific. Initially, patients were hospitalized for HDC, discharged on completion, and maintained as outpatients unless toxicities required rehospitalization (subtotal outpatient transplantation [STOT]). Once this was established as safe, a total outpatient transplant (TOT) program was developed in which patients received all of the HDC, as well as supportive care, as outpatients. Patients who declined the outpatient programs received the same HDC and supportive care as inpatients. RESULTS: In 140 of 165 (85%) HDC cycles, patients agreed to participate in one of the outpatient transplant programs. Five patients in the STOT program could not be discharged from the hospital because of toxicities that developed during HDC; thus, 135 patients were monitored the outpatient setting, 95 (70%) of whom were never readmitted. The mean +/- SEM total hospital length of stay (LOS), including all readmissions and excess days after chemotherapy, was 18.33 +/- 5.06 days for patients who refused the outpatient program, 8.22 +/- 5.76 days for patients in the STOT program, and 2.81 +/- 7.66 days for those in the TOT program (P < .001). One treatment-related death occurred in each treatment setting: day 120 inpatient, day 17 STOT, and day 110 TOT. CONCLUSION: Outpatient management of HDC/ASCR is safe and acceptable for the vast majority of patients. The STOT program resulted in significant reduction in hospital LOS, while the TOT program appears equally safe and further reduces LOS. Hospitalization for HDC/ASCR is unnecessary in most patients.

Gauging the effectiveness of extended imipramine treatment for panic disorder with agoraphobia.

BACKGROUND: Imipramine has proven efficacy for panic disorder. This study assesses the net effectiveness of systematic, open imipramine treatment in a homogenous sample of panic disorder patients with agoraphobia. METHODS: One hundred and ten consecutive patients with DSM-III-R moderate to severe panic disorder with agoraphobia were treated with a fixed regimen of imipramine 2.25 mg/kg/day for 24 weeks. No instructions or encouragement for self-directed exposure to phobic situations or other coping strategies with panic or fear were given. Assessments were conducted at the end of the 2-week placebo run-in and at weeks 8, 16, and 24 of treatment. RESULTS: Overall, 53% had a marked and stable response. Most measures revealed that substantial improvement continued beyond week 8 of treatment. Treatment success was accompanied with significant improvements in anxiety sensitivity, dysphoric mood, and functional well-being. CONCLUSIONS: These results provide a clinically relevant reference with which to compare the effectiveness of alternative treatments in providing nearly complete symptom remission in patients with primary panic disorder with agoraphobia.

Fluphenazine decanoate vs oral antipsychotics: a comparison of their effectiveness in the treatment of schizophrenia as measured by a reduction in hospital readmissions.

A significant number of chronic psychotic patients are readmitted to state mental hospitals each year due in large part to their inability or unwillingness to continue taking antipsychotic medication on a voluntary basis. This paper describes an ex post facto study comparing the effectiveness of fluphenazine decanoate, a long acting antipsychotic medication, with a variety of oral antipsychotics in reducing the number of readmissions of two groups of chronic psychotic patients to a state operated mental health facility. The results demonstrated that a group of 61 patients receiving fluphenazine decanoate had signigicantly fewer readmissions during the one year study period than did a comparison group on oral antipsychotics. The findings indicate that long acting antipsychotic medication, as part of an intensive outpatient treatment program, strongly militates against the tendency of chronic psychotic patients to discontinue treatment.