Laura Ward

Comparison Among Methods of Retinopathy Assessment (CAMRA) Study: Smartphone, Nonmydriatic, and Mydriatic Photography

PURPOSE We compared smartphone fundus photography, nonmydriatic fundus photography, and 7-field mydriatic fundus photography for their abilities to detect and grade diabetic retinopathy (DR). DESIGN This was a prospective, comparative study of 3 photography modalities. PARTICIPANTS Diabetic patients (n = 300) were recruited at the ophthalmology clinic of a tertiary diabetes care center in Chennai, India. METHODS Patients underwent photography by all 3 modalities, and photographs were evaluated by 2 retina specialists. MAIN OUTCOME MEASURES The sensitivity and specificity in the detection of DR for both smartphone and nonmydriatic photography were determined by comparison with the standard method, 7-field mydriatic fundus photography. RESULTS The sensitivity and specificity of smartphone fundus photography, compared with 7-field mydriatic fundus photography, for the detection of any DR were 50% (95% confidence interval [CI], 43-56) and 94% (95% CI, 92-97), respectively, and of nonmydriatic fundus photography were 81% (95% CI, 75-86) and 94% (95% CI, 92-96%), respectively. The sensitivity and specificity of smartphone fundus photography for the detection of vision-threatening DR were 59% (95% CI, 46-72) and 100% (95% CI, 99-100), respectively, and of nonmydriatic fundus photography were 54% (95% CI, 40-67) and 99% (95% CI, 98-100), respectively. CONCLUSIONS Smartphone and nonmydriatic fundus photography are each able to detect DR and sight-threatening disease. However, the nonmydriatic camera is more sensitive at detecting DR than the smartphone. At this time, the benefits of the smartphone (connectivity, portability, and reduced cost) are not offset by the lack of sufficient sensitivity for detection of DR in most clinical circumstances.

Sex Differences in Mental Stress‐Induced Myocardial Ischemia in Patients With Coronary Heart Disease

Background Emerging data suggest that young women with coronary heart disease (CHD) are disproportionally vulnerable to the adverse cardiovascular effects of psychological stress. We hypothesized that younger, but not older, women with stable CHD are more likely than their male peers to develop mental stress‐induced myocardial ischemia (MSIMI). Methods and Results We studied 686 patients (191 women) with stable coronary heart disease (CHD). Patients underwent 99mTc‐sestamibi myocardial perfusion imaging at rest and with both mental (speech task) and conventional (exercise/pharmacological) stress testing. We compared quantitative (by automated software) and visual parameters of inducible ischemia between women and men and assessed age as an effect modifier. Women had a more‐adverse psychosocial profile than men whereas there were few differences in medical history and CHD risk factors. Both quantitative and visual indicators of ischemia with mental stress were disproportionally larger in younger women. For each 10 years of decreasing age, the total reversibility severity score with mental stress was 9.6 incremental points higher (interaction, P<0.001) and the incidence of MSIMI was 82.6% higher (interaction, P=0.004) in women than in men. Incidence of MSIMI in women ≤50 years was almost 4‐fold higher than in men of similar age and older patients. These results persisted when adjusting for sociodemographic and medical risk factors, psychosocial factors, and medications. There were no significant sex differences in inducible ischemia with conventional stress. Conclusions Young women with stable CHD are susceptible to MSIMI, which could play a role in the prognosis of this group.

A Single-dose Zoledronic Acid Infusion Prevents Antiretroviral Therapy–induced Bone Loss in Treatment-naive HIV-infected Patients: A Phase IIb Trial

BACKGROUND Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) are associated with bone loss leading to increased fracture rate among HIV-infected individuals. ART-induced bone loss is most intense within the first 48 weeks of therapy, providing a window for prophylaxis with long-acting antiresorptives. METHODS In a phase 2, double-blind, placebo-controlled trial, we randomized 63 nonosteoporotic, ART-naive adults with HIV initiating ART with atazanavir/ritonavir + tenofovir/emtricitabine to a single zoledronic acid (ZOL) infusion (5 mg) vs placebo to determine the efficacy of ZOL in mitigating ART-induced bone loss. Plasma bone turnover markers and bone mineral density (BMD) were performed at weeks 0, 12, 24, and 48 weeks. Primary outcome was change in C-terminal telopeptide of collagen at 24 weeks. Repeated-measures analyses using mixed linear models were used to estimate and compare study endpoints. RESULTS The ZOL arm had a 65% reduction in bone resorption relative to the placebo arm at 24 weeks (0.117 ng/mL vs 0.338 ng/mL; P < .001). This effect of ZOL occurred as early as 12 weeks (73% reduction; P < .001) and persisted through week 48 (57% reduction; P < .001). The ZOL arm had an 8% higher lumbar spine BMD at 12 weeks relative to the placebo arm (P = .003), and remained 11% higher at 24 and 48 weeks. Similar trends were observed in the hip and femoral neck. CONCLUSIONS A single dose of ZOL administered at ART initiation prevented ART-induced bone loss through the first 48 weeks of ART, the period when ART-induced bone loss is most pronounced. Validation of these results in larger multicenter randomized clinical trials is warranted. CLINICAL TRIALS REGISTRATION NCT01228318.

Telomere Shortening, Regenerative Capacity, and Cardiovascular Outcomes

Rationale: Leukocyte telomere length (LTL) is a biological marker of aging, and shorter LTL is associated with adverse cardiovascular outcomes. Reduced regenerative capacity has been proposed as a mechanism. Bone marrow–derived circulating progenitor cells are involved in tissue repair and regeneration. Objective: Main objective of this study was to examine the relationship between LTL and progenitor cells and their impact on adverse cardiovascular outcomes. Methods and Results: We measured LTL by quantitative polymerase chain reaction in 566 outpatients (age: 63±9 years; 76% men) with coronary artery disease. Circulating progenitor cells were enumerated by flow cytometry. After adjustment for age, sex, race, body mass index, smoking status, and previous myocardial infarction, a shorter LTL was associated with a lower CD34+ cell count: for each 10% shorter LTL, CD34+ levels were 5.2% lower (P<0.001). After adjustment for the aforementioned factors, both short LTL (<Q1) and low CD34+ levels (<Q1) predicted adverse cardiovascular outcomes (death, myocardial infarction, coronary revascularization, or cerebrovascular events) independently of each other, with a hazard ratio of 1.8 and 95% confidence interval of 1.1 to 2.0, and a hazard ratio of 2.1 and 95% confidence interval of 1.3 to 3.0, respectively, comparing Q1 to Q2–4. Patients who had both short LTL (<Q1) and low CD34+ cell count (<Q1) had the greatest risk of adverse outcomes (hazard ratio =3.5; 95% confidence interval, 1.7–7.1). Conclusions: Although shorter LTL is associated with decreased regenerative capacity, both LTL and circulating progenitor cell levels are independent and additive predictors of adverse cardiovascular outcomes in coronary artery disease patients. Our results suggest that both biological aging and reduced regenerative capacity contribute to cardiovascular events, independent of conventional risk factors.

Written Informed Consent for Computed Tomography of the Abdomen/Pelvis is Associated with Decreased CT Utilization in Low-Risk Emergency Department Patients

Introduction The increasing rate of patient exposure to radiation from computerized tomography (CT) raises questions about appropriateness of utilization. There is no current standard to employ informed consent for CT (ICCT). Our study assessed the relationship between informed consent and CT utilization in emergency department (ED) patients. Methods An observational multiphase before-after cohort study was completed from 4/2010–5/2011. We assessed CT utilization before and after (Time I/Time II) the implementation of an informed consent protocol. Adult patients were included if they presented with symptoms of abdominal/pelvic pathology or completed ED CT. We excluded patients with pregnancy, trauma, or altered mental status. Data on history, exam, diagnostics, and disposition were collected via standard abstraction tool. We generated a multivariate logistic model via stepwise regression, to assess CT utilization across risk groups. Logistic models, stratified by risk, were generated to include study phase and a propensity score that controlled for potential confounders of CT utilization. Results 7,684 patients met inclusion criteria. In PHASE 2, there was a 24% (95% CI [10–36%]) reduction in CT utilization in the low-risk patient group (p<0.002). ICCT did not affect CT utilization in the high-risk group (p=0.16). In low-risk patients, the propensity score was significant (p<0.001). There were no adverse events reported during the study period. Conclusion The implementation of ICCT was associated with reduced CT utilization in low-risk ED patients. ICCT has the potential to increase informed, shared decision making with patients, as well as to reduce the risks and cost associated with CT.

Hemodynamic, catecholamine, vasomotor and vascular responses: Determinants of myocardial ischemia during mental stress

AIMS Mental stress-induced myocardial ischemia (MSIMI) in patients with coronary artery disease (CAD) is associated with adverse cardiovascular outcomes. We aim to assess hemodynamic, neuro-hormonal, endothelial, vasomotor and vascular predictors of MSIMI. METHODS AND RESULTS We subjected 660 patients with stable CAD to 99mTc sestamibi myocardial perfusion imaging at rest, with mental (speech task) and with conventional (exercise/pharmacological) stress. Endothelium-dependent flow-mediated dilation (FMD), microvascular reactivity [reactive hyperemia index (RHI)] and arterial stiffness [pulse wave velocity (PWV)] were measured at rest and 30-min after mental stress. The digital microvascular vasomotor response during mental stress was assessed using peripheral arterial tonometry (PAT). A total of 106(16.1%) patients had MSIMI. Mental stress was accompanied by significant increases in rate-pressure-product (heart rate x systolic blood pressure; RPP), epinephrine levels and PWV, and significant decreases in FMD and PAT ratio denoting microvascular constriction. In comparison to those with no MSIMI, patients with MSIMI had higher hemodynamic and digital vasoconstrictive responses (p<0.05 for both), but did not differ in epinephrine, endothelial or macrovascular responses. Only presence of ischemia during conventional stress (OR of 7.1, 95%CI of 4.2, 11.9), high hemodynamic response (OR for RPP response≥vs<ROC cutoff of 1.8, 95%CI of 1.1, 2.8), and high digital vasoconstriction (OR for PAT ratio<vs≥ROC cutoff of 2.1, 95%CI of 1.3, 3.3) were independent predictors of MSIMI. CONCLUSION Ischemia during conventional stress testing and hemodynamic and vasoconstrictive responses to mental stress can help predict subjects with CAD at greater risk of developing MSIMI.

Sex Differences in Hemodynamic and Microvascular Mechanisms of Myocardial Ischemia Induced by Mental Stress

Objective— To investigate sex-specific vascular mechanisms for mental stress-induced myocardial ischemia (MSIMI). Approach and Results— Baseline data from a prospective cohort study of 678 patients with coronary artery disease underwent myocardial perfusion imaging before and during a public speaking stressor. The rate-pressure product response was calculated as the difference between the maximum value during the speech minus the minimum value during rest. Peripheral vasoconstriction by peripheral arterial tonometry was calculated as the ratio of pulse wave amplitude during the speech over the resting baseline; ratios <1 indicate a vasoconstrictive response. MSIMI was defined as percent of left ventricle that was ischemic and as a dichotomous variable. Men (but not women) with MSIMI had a higher rate-pressure product response than those without MSIMI (6500 versus 4800 mm Hg bpm), whereas women (but not men) with MSIMI had a significantly lower peripheral arterial tonometry ratio than those without MSIMI (0.5 versus 0.8). In adjusted linear regression, each 1000-U increase in rate-pressure product response was associated with 0.32% (95% confidence interval, 0.22–0.42) increase in inducible ischemia among men, whereas each 0.10-U decrease in peripheral arterial tonometry ratio was associated with 0.23% (95% confidence interval, 0.11–0.35) increase in inducible myocardial ischemia among women. Results were independent of conventional stress-induced myocardial ischemia. Conclusions— Women and men have distinct cardiovascular reactivity mechanisms for MSIMI. For women, stress-induced peripheral vasoconstriction with mental stress, and not increased hemodynamic workload, is associated with MSIMI, whereas for men, it is the opposite. Future studies should examine these pathways on long-term outcomes.

Determinants and experiences of repeat pregnancy among HIV-positive Kenyan women - A mixed-methods analysis

Objective To identify factors associated with repeat pregnancy subsequent to an index pregnancy among women living with HIV (WLWH) in western Kenya who were enrolled in a 24-month phase-II clinical trial of triple-ART prophylaxis for prevention of mother-to-child transmission, and to contextualize social and cultural influences on WLWH’s reproductive decision making. Methods A mixed-methods approach was used to examine repeat pregnancy within a 24 month period after birth. Counselor-administered questionnaires were collected from 500 WLWH. Forty women (22 with a repeat pregnancy; 18 with no repeat pregnancy) were purposively selected for a qualitative interview (QI). Simple and multiple logistic regression analyses were performed for quantitative data. Thematic coding and saliency analysis were undertaken for qualitative data. Results Eighty-eight (17.6%) women had a repeat pregnancy. Median maternal age was 23 years (range 15-43 years) and median gestational age at enrollment was 34 weeks. In multiple logistic regression analyses, living in the same compound with a husband (adjusted odds ratio (AOR): 2.33; 95% confidence interval (CI): 1.14, 4.75) was associated with increased odds of repeat pregnancy (p ≤ 0.05). Being in the 30-43 age group (AOR: 0.25; 95% CI: 0.07, 0.87), having talked to a partner about family planning (FP) use (AOR: 0.53; 95% CI: 0.29, 0.98), and prior usage of FP (AOR: 0.45; 95% CI: 0.25, 0.82) were associated with a decrease in odds of repeat pregnancy. QI findings centered on concerns about modern contraception methods (side effects and views that they ‘ruined the womb’) and a desire to have the right number of children. Religious leaders, family, and the broader community were viewed as reinforcing cultural expectations for married women to have children. Repeat pregnancy was commonly attributed to contraception failure or to lack of knowledge about post-delivery fertility. Conclusions In addition to cultural context, reproductive health programs for WLWH may need to address issues related to living circumstances and the possibility that reproductive-decision making may extend beyond the woman and her partner.

Phase I dose-escalation trial of intravaginal curcumin in women for cervical dysplasia

Background This is a Phase I trial demonstrating safety and tolerability of intravaginal curcumin for future use in women with cervical neoplasia. Objective The objective of this study was to assess the safety, tolerability, and pharmacokinetics of intravaginal curcumin in healthy women. Study design We conducted a 3+3 dose-escalation Phase I trial in a group of women aged 18–45 years. Thirteen subjects were given one of four doses of curcumin powder (500 mg, 1,000 mg, 1,500 mg, and 2,000 mg) packed in gelatin capsules, which was administered intravaginally daily for 14 days. The primary end point for this study was safety based on severe adverse events regarding laboratory toxicity, clinical findings, and colposcopic abnormalities. We administered an acceptability questionnaire to assess product experience and attributes. Results No dose-limiting toxicities (0/13) were experienced (95% confidence interval: 0.0%–22.8%) in this study. The pharmacokinetics data demonstrated that curcumin and curcumin conjugates were not measurable in the serum and negligible in the urine of the study participants. Although 23 adverse events occurred during the course of the trial, all events were grade I based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and were resolved by the end of the study in an average of 9 days. Fifty-six percent of the adverse events were related to the study drug, which included genital pruritus (23% of subjects), vaginal discharge (100%), vaginal dryness (15%), abnormal prothrombin (23%), and hypokalemia (8%). Conclusion Intravaginal curcumin was well tolerated by all subjects and safe. In this Phase I trial, there were no severe adverse events observed at any of the administered dose levels. All adverse events were grade I and did not result in early termination of the study. There was no evidence of systemic absorption or significant local absorption of intravaginally administered curcumin.

Synthetic mesh vs. allograft extensor mechanism reconstruction in total knee arthroplasty — A systematic review of the literature and meta-analysis

BACKGROUND Extensor mechanism disruption after total knee arthroplasty (TKA) is a devastating complication. Reconstruction with allograft and synthetic mesh has been described. However, these reports have typically been small case series, and controversy exists with regard to which reconstruction technique is optimal. METHODS The authors performed a systematic review using PUBMED, MEDLINE, EMBASE, BIOSIS, Clinicaltrials.gov, and Cochrane Database of Systematic Reviews identifying 14 articles meeting inclusion criteria and producing 204 knees for comparison. Studies with repairs performed under full knee extension were included. Case reports and non-English studies were excluded. Available demographics and clinical outcome data were collected from each study. Appropriate statistical analysis was performed to compare the variables. RESULTS Baseline demographics and patient complexity were similar between the two cohorts. Reconstruction success rates (76% allograft vs. 74% mesh), average time to diagnosis/treatment, Knee Society Scores (KSS), knee range of motion/extensor lag, and complication rates yielded no statistical difference. Synthetic mesh was used more frequently with concomitant revision of components. DISCUSSION This systematic review shows equivalent success of allograft and synthetic mesh with approximately 25% failure rate in both groups. Periprosthetic joint infection remains a common and significant complication and reason for failure in both groups. Overall, synthetic mesh showed equivalent extensor mechanism reconstruction success as allograft but with much lower cost, near universal availability, lack of disease transmission, and potential for diminishing graft stretch-out. Future research in larger case series or comparative study is needed to help aid in management of this largely unsolved problem in total knee reconstruction.