Newborn Hearing Screenings in Human Immunodeficiency Virus-Exposed Uninfected Infants.

Perinatal HIV infection and congenital cytomegalovirus (CMV) infection may increase the risk for hearing loss. We examined 1,435 infants enrolled in the Surveillance Monitoring of ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) network, a prospective study of the safety of in utero antiretroviral (ARV) exposures. We determined the proportion of perinatally HIV-exposed uninfected (HEU) newborns who were referred for additional hearing testing, and evaluated the association between in utero ARV exposures and newborn hearing screening results. Using a nested case-control design, we also examined congenital CMV infection in infants with and without screening referral. Congenital CMV infection was determined based on CMV DNA detection using a nested PCR assay in peripheral blood mononuclear cells obtained within 14 days of birth. Among the 1,435 infants (70% black, 31% Hispanic, 51% male), 45 (3.1%) did not pass the hearing screen and were referred for further hearing testing. Based on exact logistic regression models controlling for maternal use of tobacco and ototoxic medications, first trimester exposure to Tenofovir was associated with lower odds of a newborn hearing screening referral [adjusted odds ratio (aOR) = 0.41, 95% confidence interval (CI): 0.14-1.00]. Exposure to Atazanavir was linked to higher odds of newborn screening referral, although not attaining significance [aOR = 1.84, 95% CI: 0.92-3.56]. Maternal ARV use may have varying effects on newborn hearing screenings. These results highlight the importance for audiologists to be knowledgeable of in utero ARV exposures in HEU children because of the possibility of higher referrals in these children.

Effect of HIV genotypic drug resistance testing on the management and clinical course of HIV-infected children and adolescents.

The clinical utility of genotypic drug resistance testing (DRT) in HIV-infected children on antiretroviral therapy (ART) is not well understood. HIV-infected patients aged <19 years undergoing DRT for virological failure were retrospectively enrolled. Indications for DRT and changes in HIV RNA load were recorded. Between January 2000 and December 2006, 57 patients had DRT. The most common indication for DRT was poor ART adherence (57.7% of patients). ART was changed in 50.9% of patients after DRT. Poor adherence was cited by clinicians for not changing ART significantly more often than any other reason (47.3%, P < 0.001). After DRT, significant improvement in HIV RNA load occurred independent of ART changes, though patients whose ART was modified were more likely to become undetectable (31.5% versus 7.0%, P < 0.001). Poor adherence was a significant factor for ordering DRT and for not changing ART in HIV-infected children.

Driven dynamics and rotary echo of a qubit tunably coupled to a harmonic oscillator.

We have investigated the driven dynamics of a superconducting flux qubit that is tunably coupled to a microwave resonator. We find that the qubit experiences an oscillating field mediated by off-resonant driving of the resonator, leading to strong modifications of the qubit Rabi frequency. This opens an additional noise channel, and we find that low-frequency noise in the coupling parameter causes a reduction of the coherence time during driven evolution. The noise can be mitigated with the rotary-echo pulse sequence, which, for driven systems, is analogous to the Hahn-echo sequence.

Low rate of CMV end-organ disease in HIV-infected patients despite low CD4+ cell counts and CMV viremia: results of ACTG protocol A5030.

PURPOSE: To describe cytomegalovirus (CMV) end-organ disease (EOD) rate in AIDS patients with low CD4+ cell count despite HAART who were enrolled in a randomized, placebo-controlled trial of preemptive valganciclovir (VGCV) to prevent CMV EOD in those with CMV viremia. METHODS: Subjects (N = 338) were HIV-infected with CD4+ count <100 cells/mm3, plasma HIV RNA >400 copies/mL, and on stable or no HAART. All underwent plasma CMV DNA PCR testing every 8 weeks (Step 1); those with detectable CMV DNA were randomized to VGCV or placebo (Step 2). RESULTS: Plasma CMV DNA was detected in 68 (20%), of whom 4 developed CMV EOD. During Step 1, 53 died. Of the 47 who entered Step 2 (24 VGCV, 23 placebo), CMV EOD was diagnosed in 10 (4 VGCV, 6 placebo) and 15 died (7 VGCV, 8 placebo). Of those randomized to placebo, 14% were diagnosed with CMV EOD at 12 months. CONCLUSIONS: We observed a lower CMV EOD rate among subjects receiving HAART than predicted based on published literature. However, mortality was high in this study. Our findings suggest that preemptive anti-CMV therapy in patients with persistently low CD4+ cell counts in the current treatment era may not be warranted given the low incidence of CMV EOD and high all-cause mortality observed in this study population.

Silicon waveguide infrared photodiodes with >35 GHz bandwidth and phototransistors with 50 AW-1 response.

SOI CMOS compatible Si waveguide photodetectors are made responsive from 1100 to 1750 nm by Si+ implantation and annealing. Photodiodes have a bandwidth of >35 GHz, an internal quantum efficiency of 0.5 to 10 AW-1, and leakage currents of 0.5 nA to 0.5 microA. Phototransistors have an optical response of 50 AW-1 with a bandwidth of 0.2 GHz. These properties are related to carrier mobilities in the implanted Si waveguide. These detectors exhibit low optical absorption requiring lengths from <0.3 mm to 3 mm to absorb 50% of the incoming light. However, the high bandwidth, high quantum efficiency, low leakage current, and potentially high fabrication yields, make these devices very competitive when compared to other detector technologies.

CMOS-compatible dual-output silicon modulator for analog signal processing.

A broadband, Mach-Zehnder-interferometer based silicon optical modulator is demonstrated, with an electrical bandwidth of 26 GHz and V(pi)L of 4 V.cm. The design of this modulator does not require epitaxial overgrowth and is therefore simpler to fabricate than previous devices with similar performance.

Arginine deprivation as a targeted therapy for cancer.

Certain cancers may be auxotrophic for a particular amino acid, and amino acid deprivation is one method to treat these tumors. Arginine deprivation is a novel approach to target tumors which lack argininosuccinate synthetase (ASS) expression. ASS is a key enzyme which converts citrulline to arginine. Tumors which usually do not express ASS include melanoma, hepatocellular carcinoma, some mesotheliomas and some renal cell cancers. Arginine can be degraded by several enzymes including arginine deiminase (ADI). Although ADI is a microbial enzyme from mycoplasma, it has high affinity to arginine and catalyzes arginine to citrulline and ammonia. Citrulline can be recycled back to arginine in normal cells which express ASS, whereas ASS(-) tumor cells cannot. A pegylated form of ADI (ADI-PEG20) has been formulated and has shown in vitro and in vivo activity against melanoma and hepatocellular carcinoma. ADI-PEG20 induces apoptosis in melanoma cell lines. However, arginine deprivation can also induce ASS expression in certain melanoma cell lines which can lead to in vitro drug resistance. Phase I and II clinical trials with ADI-PEG20 have been conducted in patients with melanoma and hepatocellular carcinoma, and antitumor activity has been demonstrated in both cancers. This article reviews our laboratory and clinical experience as well as that from others with ADI-PEG20 as an antineoplastic agent. Future direction in utilizing this agent is also discussed.

Poor outcome is associated with delayed tuberculosis diagnosis in HIV-infected children in Baja California, Mexico.

OBJECTIVE: To describe the morbidity and mortality associated with tuberculosis (TB) in human immunodeficiency virus (HIV) infected children in Baja California, Mexico. METHODS: Retrospective review of the medical records of all children with perinatally acquired HIV infection evaluated at Tijuana General Hospital with a diagnosis of TB between 1998 and 2007. The Stegen-Toledo (ST) clinical criteria for the diagnosis of TB were used. RESULTS: A total of 73 HIV-infected children were followed during the study period. Thirteen (18%) children were diagnosed with TB; one was confirmed by culture to be positive. Among these children, the mean ages at HIV and TB diagnosis were respectively 3.6 and 5.3 years. The mean ST score was 8.1; 10/13 had a score of >or=7, or highly probable TB. There were a cumulative 29 hospital admissions prior to TB diagnosis; 24 of these were due to pneumonia. The mean duration of symptoms at TB diagnosis was 73 days. The most common symptoms were cough (92%) and anorexia (85%). Seven patients (54%) had disseminated TB and five (39%) died as a consequence of TB. CONCLUSIONS: We observed high morbidity, hospital utilization and high mortality associated with TB among HIV-infected children in Baja California.

Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics.

OBJECTIVES: To determine the impact of pregnancy on the pharmacokinetics (PK) of nevirapine (NVP) during chronic dosing in HIV-infected women and appropriate NVP dosing in this population. METHODS: Twenty-six pregnant women participating in two open-label Pediatric AIDS Clinical Trials Group studies (P1022 and P1026S) were evaluated. Each patient received 200 mg NVP every 12 h and had PK evaluations during the second or third trimester; these evaluations were repeated postpartum. Paired maternal and cord blood NVP concentrations were collected at delivery in nine patients. Ante- and postpartum comparisons were made using paired t-tests and using a 'bioequivalence' approach to determine confidence interval (CI). RESULTS: The average NVP Area Under the Curve (AUC) was 56 +/- 13 mcg(*)h/mL antepartum and 61 +/- 15 mcg(*)h/mL postpartum. The typical parameters +/- standard error were apparent clearance (CL/F)=3.51 +/- 0.18 L/h and apparent volume of distribution (Vd/F)=121 +/- 19.8 L. There were no significant differences between antepartum and postpartum AUC or pre-dose concentrations. The AUC ratio was 0.90 with a 90% CI of the mean equal to 0.80-1.02. The median (+/- standard deviation) cord blood to maternal NVP concentration ratio was 0.91 +/- 0.90. CONCLUSIONS: Pregnancy does not alter NVP PK and the standard dose (200 mg every 12 h) is appropriate during pregnancy.

Pharmacokinetics and pharmacodynamics of efavirenz and nelfinavir in HIV-infected children participating in an area-under-the-curve controlled trial.

Fifty human immunodeficiency virus (HIV)-infected children participated in an area-under-the plasma concentration-time curve (AUC)-controlled trial of efavirenz and nelfinavir. Pharmacokinetic evaluations were performed at weeks 2, 6, and 56. Efavirenz and nelfinavir doses were adjusted to achieve AUC values of 60-120 and > or = 10 mg h/l, respectively. Thirty-seven (74%) children met the efavirenz target and 41 (82%) the nelfinavir by week 10. Children with AUC values for both drugs above the first quartile were more likely to reach < 400 copies/ml of HIV RNA at week 8. Efavirenz and nelfinavir oral clearance increased 37 and 62% from weeks 2 to 56, respectively, in 34 children who continued on therapy at week 56. AUC values at week 56 were not different between children who did or did not have HIV RNA < 400 copies/ml. Dose adjustment to achieve specific AUC values in these children reduced the risk of suboptimal exposure and achieved high rates of virologic suppression.

Prevalence of primary HIV-1 drug resistance in pregnant women and in newly diagnosed adults at Tijuana General Hospital, Baja California, Mexico.

At Tijuana General Hospital, between March 2003 and June 2005, pregnant women and other adults, recently identified as HIV infected, antiretroviral naïve, were enrolled to examine the prevalence of primary HIV drug resistance. All subjects had the Calypte HIV-1 BED Incidence enzyme immunoassay test to identify recent infection. Genotypic analysis of HIV-1 protease and reverse transcriptase regions in plasma was performed. Forty-six subjects participated, eight (17%) men, 38 (83%) women. Ten (22%) subjects were classified as having recent HIV infection. HIV genotype was performed in 41 subjects. One subject (2.5%) had a major mutation in the reverse transcriptase region (K219Q) conferring zidovudine resistance, one had a minor mutation at V118I (2.5%) and two subjects (5%) had minor mutation (V179D) associated with non-nucleoside reverse transcriptase inhibitor resistance. There were no major protease inhibitor-associated mutations but minor mutations were common. The prevalence of primary HIV drug resistance in Baja California is low.

Performance of rapid HIV testing using Determine HIV-1/2 for the diagnosis of HIV infection during pregnancy in Tijuana, Baja California, Mexico.

The aim of this study was to evaluate the performance of the rapid antibody test Determine HIV-1/2, in pregnant women at Tijuana General Hospital. Pregnant women seeking prenatal care or admitted in labour had blood drawn for a rapid HIV test (Determine HIV-1/2), enzyme immunoassay (EIA) and Western blot. Between March and November 2003, 1068 women in labour and 1529 women in prenatal care were enrolled. The sensitivity, specificity, positive and negative predictive values were 100%, 99.8%, 77% and 100%, respectively. For women in labour, the mean time between blood collection and rapid test results was 92 minutes (range: 20-205 minutes) compared with 41 hours (range 24-120 hours) for HIV EIA (P = 0.012). All HIV-exposed infants received oral zidovudine. These findings indicate that the rapid test Determine HIV-1/2 has a high sensitivity and specificity in pregnant women. Rapid HIV testing greatly diminishes the time to diagnosis and enables prompt intervention with antiretrovirals at delivery.

All silicon infrared photodiodes: photo response and effects of processing temperature.

CMOS compatible infrared waveguide Si photodiodes are made responsive from 1100 to 1750 nm by Si(+) implantation and annealing. This article compares diodes fabricated using two annealing temperatures, 300 and 475 degrees C. 0.25-mm-long diodes annealed to 300 degrees C have a response to 1539 nm radiation of 0.1 A W-(-1) at a reverse bias of 5 V and 1.2 A W(-1) at 20 V. 3-mm-long diodes processed to 475 degrees C exhibited two states, L1 and L2, with photo responses of 0.3 +/-0.1 A W(-1) at 5 V and 0.7 +/-0.2 A W(-1) at 20 V for the L1 state and 0.5 +/-0.2 A W(-1) at 5 V and 4 to 20 A W(-1)-1 at 20 V for the L2 state. The diodes can be switched between L1 and L2. The bandwidths vary from 10 to 20 GHz. These diodes will generate electrical power from the incident radiation with efficiencies from 4 to 10 %.

Is the St. Jude Medical mechanical valve an appropriate choice for elderly patients?: A long-term retrospective study measuring quality of life.

BACKGROUND AND AIM OF THE STUDY: The selection of a suitable valve substitute in patients requiring valvular heart surgery is an important element in the preoperative decision-making process between cardiologist, surgeon, and patient. Controversy persists regarding the use of mechanical valves in the elderly. With the population living longer, reoperative risk becomes of paramount importance. Quality of life (QOL) considerations are often as important to the patient as longevity. The influence of mechanical valve replacement on QOL in elderly patients has not been well documented. METHODS: Between June 1981 and December 1999, a total of 1,125 consecutive patients aged > or = 65 years (582 men, 543 women; mean age 71.4 +/- 4.9 years) underwent valve replacement with at least one St. Jude Medical (SJM) mechanical valve. Preoperatively, 138 patients (12.3%) were in NYHA class II, 775 (68.9%) in class III, and 212 (18.8%) in class IV. In 535 patients (47.6%), coronary artery disease required surgical intervention. Survivors were administered the Short Form (SF)-36 QOL Survey at follow up, which was 96.1% complete. RESULTS: Hospital mortality was 7.6% (85/1,125). Mean follow up was 5.9 years (range: 9 months to 18.4 years). Mean (+/- SEM) actuarial survival was 70.6 +/- 1.4% at five years, and 40.6 +/- 2.0% at 10 years. Male patients scored significantly higher on the SF-36 than controls in physical (p = 0.012) and mental health (p = 0.004). Comparing female patients with controls revealed no significant difference in physical health; however, they scored higher in mental health than controls (p = 0.001). CONCLUSION: The study results clearly demonstrate that heart surgery in the elderly with the SJM mechanical valve can be accomplished with acceptable hospital mortality, morbidity, and excellent long-term results. Moreover, long-term QOL in elderly patients with a SJM valve can be expected to meet or exceed that of age- and gender-matched controls.

The safety of discontinuation of maintenance therapy for cytomegalovirus (CMV) retinitis and incidence of immune recovery uveitis following potent antiretroviral therapy.

BACKGROUND: Reconstitution of immune function during potent antiretroviral therapy can prompt discontinuation of maintenance cytomegalovirus (CMV) therapy but has also been associated with sight-threatening inflammatory conditions including immune recovery uveitis (IRU). METHOD: Patients with inactive CMV retinitis and a CD4+ cell count above 100/mm3, receiving CMV therapy and stable combination antiretroviral therapy, were assigned to one of two groups based on willingness to discontinue CMV therapy. RESULTS: Thirty-eight participants were enrolled: 28 discontinued anti-CMV therapy (Group 1) and 10 continued CMV treatment (Group 2). Median on-study follow-up was 16 months. One Group 1 participant who experienced an increase in plasma HIV viral load and a decline in CD4+ cell count developed confirmed progression of CMV retinitis. Progression or reactivation CMV retinitis was not observed among Group 2. IRU was present at study entry in 3 participants. Six participants in Group 1 and 3 participants in Group 2 developed IRU on-study. CMV viremia was not detected in any participants, and urinary shedding of CMV was intermittent. CONCLUSION: Recurrence of CMV retinitis following discontinuation of anti-CMV therapy among patients with antiretroviral-induced increases in CD4+ cell count was rare. However, IRU was common in both those who maintained and discontinued anti-CMV therapy.

Omalizumab: efficacy in allergic disease.

Asthma and allergic rhinitis are common conditions that have a substantial impact on patient quality of life, severely disrupting physical, emotional and social functioning. These diseases share many pathophysiological characteristics and recent research has provided evidence that a strong causal relationship exists between allergy and both asthma and allergic rhinitis. As a root cause of allergic diseases of the airways, immunoglobulin E (IgE) represents an appropriate target for the development of new therapies. Omalizumab (Xolair) is a recombinant humanized monoclonal anti-IgE antibody that has demonstrated efficacy in allergic asthma and other IgE-related allergic illnesses. In three pivotal, placebo-controlled trials in patients with moderate-to-severe allergic asthma, omalizumab provided effective disease control, significantly reducing exacerbations while improving quality of life. Additionally, omalizumab reduced the need for unscheduled outpatient visits, emergency room visits and hospitalizations. Omalizumab was particularly useful as add-on treatment for patients with poorly controlled severe asthma. Similar benefits were reported in patients with seasonal or perennial allergic rhinitis. Omalizumab significantly improved disease symptoms and reduced the use of rescue antihistamines. In patients with concomitant asthma and perennial allergic rhinitis, omaliuzumab significantly prevented asthma exacerbations and improved quality of life compared with placebo. Taken together, these results suggest that omalizumab represents an important clinical advance in the management of allergic disease.

Associations of CCR5, CCR2, and stromal cell-derived factor 1 genotypes with human immunodeficiency virus disease progression in patients receiving nucleoside therapy.

Genotype data for CCR5, CCR2, and stromal cell-derived factor 1 (SDF-1) were obtained from 354 human immunodeficiency virus type 1 (HIV-1)-positive subjects who were being treated with nucleosides. Associations with HIV-1 load, HIV syncytium-inducing (SI) phenotype, CD4 cell count, and disease progression were analyzed. No differences in HIV-1 load or CD4 cell count were observed between wild type (+) and variant genotypes. Changes from non-SI to SI viral phenotype were more frequent in heterozygotes with a 32-bp deletion (Delta32) in the CCR5 gene than in + homozygotes (40% vs. 7%; P=.01). In a multivariate analysis, heterozygous CCR5 Delta32 was associated with reduced hazard of progression (hazard ratio, 0.32; P=.02). Subjects homozygous for the SDF-1 3'A variant had more-rapid disease progression (P=.008). The SDF-1 homozygous 3'A variant was related to more-rapid disease progression, and CCR5 Delta32 was associated with reduced rates of hazard for disease progression in nucleoside-treated subjects.

Predictors of virologic and clinical outcomes in HIV-1-infected patients receiving concurrent treatment with indinavir, zidovudine, and lamivudine. AIDS Clinical Trials Group Protocol 320.

BACKGROUND: A substantial proportion of patients with HIV infection will not respond to antiretroviral therapy. Early predictors of response to treatment are needed to identify patients who are at risk for treatment failure. OBJECTIVE: To determine predictors of virologic and clinical response to indinavir, zidovudine, and lamivudine therapy. DESIGN: Observational analysis of one treatment group in a phase III trial. SETTING: 40 AIDS Clinical Trials units. PATIENTS: 489 patients receiving indinavir, zidovudine, and lamivudine who had 1) a CD4 count of 0.200 x 10(9) cells/L or less after 8 or more weeks of study therapy and 2) plasma HIV-1 RNA measurements obtained at baseline and week 8. MEASUREMENTS: HIV-1 RNA level and CD4 cell count at weeks 0, 4, 8, 24, and 40. Clinical progression was defined as a new AIDS-defining illness or death. RESULTS: Patients' levels of HIV-1 RNA at the 8th study week of therapy predicted whether patients would achieve virologic suppression to below 500 (or 50) copies/mL at study week 24. An HIV-1 RNA level less than 500 copies/mL at week 24 was achieved in 71% of patients whose level at week 8 had been less than 500 copies/mL, 53% of those with a level of 500 copies/mL or more and at least 2-log(10) copies/mL reduction since baseline, 29% of those with a level of 500 copies/mL or more with a 1- to 1.99-log(10) copies/mL reduction, and 9% of those with a level of 500 copies/mL or greater and less than 1-log(10) copies/mL reduction since baseline (P < 0.001). HIV-1 RNA level at week 8 also predicted clinical progression. HIV-1 disease progressed in 2.2% of the patients with a week-8 HIV-1 RNA level less than 500 copies/mL, 2.3% of patients with 500 copies/mL or greater and at least 2-log(10) copies/mL reduction since baseline, 4.9% of patients with 500 copies/mL or greater and 1- to 1.99-log(10) copies/mL reduction since baseline, and 10.6% of patients with 500 copies/mL or greater and less than 1-log(10) copies/mL decrease since baseline (P = 0.009). After adjustment for HIV-1 RNA level, patients with a higher week-8 CD4 cell count were more likely to have a week-24 HIV-1 RNA level less than 500 copies/mL (relative risk for patients with a week-8 CD4 count >/= 0.10 x 10(9) cells/L, 1.47 [95% CI, 1.00 to 2.16] compared with <0.050 x 10(9) cells/L; relative risk for patients with a week-8 CD4 count of 0.05 to 0.099 x 10(9) cells/L, 0.98 [CI, 0.61 to 1.57] compared with <0.050 x 10(9) cells/L). After adjustment for HIV-1 RNA level, patients with a week-8 CD4 count of 0.05 x 10(9) cells/L or greater (compared with <0.05 x 10(9) cells/L) had a decreased hazard for clinical progression (hazard ratio, 0.25 [CI, 0.09 to 0.67]). CONCLUSIONS: The HIV-1 RNA level and CD4 cell count achieved at 8 weeks of treatment are important predictors of subsequent virologic and clinical outcomes.

Human immunodeficiency virus type 1 (HIV-1) gp120-specific antibodies in neonates receiving an HIV-1 recombinant gp120 vaccine.

Infants born to human immunodeficiency virus type 1 (HIV-1)-infected mothers were immunized at birth and at ages 4, 12, and 20 weeks with low-, medium-, or high-dose recombinant gp120 vaccine with MF59 adjuvant (HIV-1(SF-2); n=52) or with MF59 alone as a placebo (n=9). An accelerated schedule (birth and ages 2, 8, and 20 weeks) was used for an additional 10 infants receiving the defined optimal dose and for 3 infants receiving placebo. At 24 weeks, anti-gp120 ELISA titers were greater for vaccine-immunized than for placebo-immunized infants on both schedules, and 87% of vaccinees had a vaccine-induced antibody response. At 12 weeks, antibody titers of infants on the accelerated vaccine schedule exceeded those of infants receiving placebo (4949 vs. 551; P=.01), and 63% of the vaccinees met the response criteria. Thus, an accelerated schedule of gp120 vaccinations generated an antibody response to HIV-1 envelope distinct from transplacental maternal antibody by age 12 weeks. These results provide support for further studies of vaccine strategies to prevent mother-to-infant HIV-1 transmission.