The associations of CD4 count, CD4/CD8 ratio, and HIV viral load with survival from non-small cell lung cancer in persons living with HIV.

HIV status may influence survival from non-small cell lung cancer (NSCLC). Among NSCLC patients in the Bronx, NY, we assessed (1) associations of CD4 count, CD4/CD8 ratio and HIV viral load (VL) with survival and (2) prognostic factors among persons living with HIV (PLWH). We compared survival from NSCLC diagnosis (2004-2017) between HIV-negative persons (HIV-, n=2,881) and PLWH (n=88) accounting for clinical and sociodemographic factors. HIV-survival was also compared with PLWH, dichotomized by CD4 (<200 vs. ≥200cells/µL), CD4/CD8 (median, <0.43 vs. ≥0.43) and VL (<75 vs. ≥75copies/mL) at NSCLC diagnosis. Among PLWH, we assessed the relationships of CD4, CD4/CD8, and VL with survival, adjusting for age, sex, and cancer stage. PLWH with CD4< 200cells/µL had lower survival than HIV- [hazard ratio, 95% confidence interval [HR(95%CI)]=1.86(0.98-3.55)]. Survival was similar between PLWH with CD4≥ 200cells/µL and HIV- [HR(95%CI) = 0.90(0.61-1.33)]. Results were similar when categorizing PLWH by CD4/CD8 [vs. HIV-: low CD4/CD8: HR(95%CI) = 1.74(1.07-3.89); high CD4/CD8: HR(95%CI) = 0.63(0.37-1.07)] and VL [vs. HIV-: <75copies/mL: HR(95%CI) = 0.74(0.46-1.21), ≥75copies/mL: HR(95%CI) = 1.41(0.88-2.27)]. Among PLWH, CD4< 200cells/µL was associated with worse survival [vs. CD4≥ 200cells/µL: HR(95%CI) = 2.37(1.14-4.92)]. CD4, CD4/CD8, and VL may be prognostic markers for PLWH with NSCLC, suggesting immune status may be important in NSCLC survival among PLWH.

Subclinical cardiovascular disease in HIV controller and long-term nonprogressor populations.

OBJECTIVES: Elite controllers (ECs), viraemic controllers (VCs), and long-term nonprogressors (LTNPs) control HIV viral replication or maintain CD4 T-cell counts without antiretroviral therapy, but may have increased cardiovascular disease (CVD) risk compared to HIV-uninfected persons. We evaluated subclinical carotid and coronary atherosclerosis and inflammatory biomarker levels among HIV controllers, LTNPs and noncontrollers and HIV-uninfected individuals in the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS). METHODS: We measured carotid plaque presence and common carotid artery intima-media thickness (IMT) in 1729 women and 1308 men, and the presence of coronary artery calcium and plaque in a subgroup of men. Associations between HIV control category and carotid and coronary plaque prevalences were assessed by multivariable regression analyses adjusting for demographics and CVD risk factors. Serum inflammatory biomarker concentrations [soluble CD163 (sCD163), soluble CD14 (sCD14), galectin-3 (Gal-3), galectin-3 binding protein (Gal-3BP) and interleukin (IL)-6] were measured and associations with HIV control category assessed. RESULTS: We included 135 HIV controllers (30 ECs) and 135 LTNPs in the study. Carotid plaque prevalence and carotid IMT were similar in HIV controllers, LTNPs and HIV-uninfected individuals. HIV controllers and LTNPs had lower prevalences of carotid plaque compared to viraemic HIV-infected individuals. The prevalence of coronary atherosclerosis was similar in HIV controllers/LTNPs compared to HIV-uninfected and viraemic HIV-infected men. Controllers and LTNPs had higher concentrations of sCD163 and sCD14 compared to HIV-uninfected persons. CONCLUSIONS: Subclinical CVD was similar in HIV controllers, LTNPs and HIV-uninfected individuals despite elevated levels of some inflammatory biomarkers. Future studies of HIV controllers and LTNPs are needed to characterize the risk of CVD among HIV-infected persons.

AIDS-defining opportunistic illnesses in the HAART era in New York City.

Despite widespread availability of HAART, opportunistic illnesses (OIs) still occur and result in an increased risk of mortality among persons with AIDS. We estimated the incidence of OIs among all new adult AIDS cases in New York City in 2000 overall and in demographic and clinical subgroups and identified factors associated with occurrence of an AIDS-defining OI versus AIDS diagnosis based on low CD4+ values only. In 2000, 5,451 new AIDS cases were reported to the New York City Department of Health and Mental Hygiene. Of these 27.4% (95% CI: 22.8-32.6) had at least one OI, most frequent being Pneumocystis jiroveci pneumonia (12.2%) and M. tuberculosis (5.3%); 47.1% (41.7-52.5) had a late HIV diagnosis (i.e.< or =6 months before AIDS diagnosis). Persons with a late HIV diagnosis not in recent care had a 3.5-fold increased odds (1.29-9.63) of an OI, compared to non-late testers in care. Other predictors of an OI were injection drug use and older age. We conclude that OIs remain prevalent in the HAART era and late testers not in care are especially likely to develop an OI. Our results support comprehensive HIV programs promoting early HIV testing and linkage to care to prevent OI-related morbidity and mortality.

Meta-analysis: upper gastrointestinal tolerability of valdecoxib, a cyclooxygenase-2-specific inhibitor, compared with nonspecific nonsteroidal anti-inflammatory drugs among patients with osteoarthritis and rheumatoid arthritis.

AIM: To compare the incidence of abdominal pain, dyspepsia and/or nausea associated with valdecoxib, nonspecific nonsteroidal anti-inflammatory drugs and placebo in patients with rheumatoid arthritis and osteoarthritis. METHODS: Data from five randomized, double-blind 12-week trials were pooled. Independent risk factors for abdominal pain, dyspepsia and/or nausea were also determined. RESULTS: The final analysis consisted of 4394 patients. Nonspecific nonsteroidal anti-inflammatory drug users (n = 1185) received naproxen 1000 mg/day (n = 766), ibuprofen 2400 mg/day (n = 207) or diclofenac sodium 150 mg/day (n = 212). Valdecoxib users received 10 mg/day (n = 955), 20 mg/day (n = 851) or 40 mg/day (n = 430). A total of 973 patients received placebo. The nonspecific nonsteroidal anti-inflammatory drug group was most likely to report abdominal pain or dyspepsia, while the placebo group reported the highest incidence of nausea. The most important risk factors for abdominal pain, dyspepsia and/or nausea were nonspecific nonsteroidal anti-inflammatory drug use, gastrointestinal history of nonspecific nonsteroidal anti-inflammatory drug-related intolerance or gastroduodenal ulcers, osteoarthritis diagnosis, female gender and age <65 years. CONCLUSION: This pooled analysis demonstrates a clear decrease in dyspepsia and an improvement in upper gastrointestinal tolerability for patients with osteoarthritis and rheumatoid arthritis taking valdecoxib, even at supratherapeutic doses, compared with those taking nonspecific nonsteroidal anti-inflammatory drugs over 12 weeks.

Presurgical intravenous parecoxib sodium and follow-up oral valdecoxib for pain management after laparoscopic cholecystectomy surgery reduces opioid requirements and opioid-related adverse effects.

BACKGROUND: Opioids are associated with numerous adverse effects. It is unclear if reduced postoperative opioid consumption lowers the incidence and severity of opioid-related adverse effects. This analysis -- from a multicenter, randomized, double-blind trial -- tested if the reduction of opioid consumption among patients who received intravenous preoperative parecoxib 40 mg, followed by oral valdecoxib 40 mg qd postoperatively, in Days 1-4 after outpatient laparoscopic cholecystectomy surgery, reduced opioid-related symptoms. METHODS: Patients received intravenous fentanyl for pain before discharge, and oral acetaminophen 500 mg hydrocodone 5 mg q 4-6 h prn postdischarge for up to 7 days postsurgery. Patients also received intravenous parecoxib 40 mg administered 30-45 min preoperatively, and valdecoxib 40 mg qd up to Day 4 and prn Days 5-7 postsurgery, or placebo. Patients completed an opioid-related Symptoms Distress Scale (SDS) questionnaire every 24 h for 7 days. Opioid use was converted to morphine-equivalent doses (MEDs). Clinically meaningful events (CMEs) for 12 opioid-related symptoms were assessed by three ordinal measures: frequency, severity, and bothersomeness. Reduction of CMEs on Day 1 and number of patient-days with CMEs on Days 1-4 were examined. RESULTS: Cumulative MEDs on Day 0, Day 1, and Days 1-4 were significantly lower in the parecoxib/valdecoxib group compared with the placebo group (P < 0.001). At the end of Day 1, parecoxib/valdecoxib-treated patients had significantly lower SDS scores (P < 0.02), a significantly reduced incidence of CMEs (P < 0.05), and significantly fewer patient-days with CMEs in Days 1-4 than placebo patients (P < 0.05). Patients in the parecoxib/valdecoxib group were less likely to have CMEs for multiple symptoms than those in the placebo group (P < 0.001). CONCLUSIONS: Treatment with parecoxib and valdecoxib significantly reduced the cumulative MED requirements, the incidence of opioid-related adverse effects, and patient-days with CMEs.

Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate.

Hereditary human retinal degenerative diseases usually affect the mature photoreceptor topography by reducing the number of cells through apoptosis, resulting in loss of visual function. Only one inherited retinal disease, the enhanced S-cone syndrome (ESCS), manifests a gain in function of photoreceptors. ESCS is an autosomal recessive retinopathy in which patients have an increased sensitivity to blue light; perception of blue light is mediated by what is normally the least populous cone photoreceptor subtype, the S (short wavelength, blue) cones. People with ESCS also suffer visual loss, with night blindness occurring from early in life, varying degrees of L (long, red)- and M (middle, green)-cone vision, and retinal degeneration. The altered ratio of S- to L/M-cone photoreceptor sensitivity in ESCS may be due to abnormal cone cell fate determination during retinal development. In 94% of a cohort of ESCS probands we found mutations in NR2E3 (also known as PNR), which encodes a retinal nuclear receptor recently discovered to be a ligand-dependent transcription factor. Expression of NR2E3 was limited to the outer nuclear layer of the human retina. Our results suggest that NR2E3 has a role in determining photoreceptor phenotype during human retinogenesis.

Retinal degenerations with truncation mutations in the cone-rod homeobox (CRX) gene.

PURPOSE: To define the phenotypes of retinal degenerations associated with mutations in the gene encoding CRX (cone-rod homeobox), a photoreceptor-specific transcription factor. METHODS: Heterozygotes with the E168 [delta1 bp], E168 [delta2 bp], or G217 [delta1 bp] CRXgene mutation were studied clinically, with visual function tests, including rod and cone perimetry and electroretinography (ERG), and with optical coherence tomography (OCT). RESULTS: Clinical diagnoses included autosomal dominant cone-rod dystrophy in one family (E168 [delta1 bp] mutation) and simplex Leber congenital amaurosis in two families (E168 [delta2 bp], G217 [delta1 bp] mutations). In the family with the E168 [delta1 bp] mutation, two siblings had relatively mild disease expression in the third decade of life. The central retinas of these two patients had profound loss of rod and short wavelength cone function; long/middle wavelength cone thresholds were elevated at fixation, but there were greater paracentral than central abnormalities. Peripheral retinal dysfunction was evident by psychophysics and by maximum amplitude loss for rod- and cone-isolated ERG photoreceptor responses. OCT cross-sectional reflectance images showed decreased central retinal thickness consistent with photoreceptor loss. An additional member of this family (E168 [delta1 bp] mutation) and two other patients (representing E168 [delta2 bp] and G217 [delta1 bp] mutations) had a severe phenotype with retina-wide loss of function and islands of function remaining only in the temporal periphery. CONCLUSIONS: Truncation mutations in CRX are associated with retinopathies that share phenotypic features but vary in disease severity. The disease mechanism could involve abnormal photoreceptor development compounded by a disturbance in the maintenance of photoreceptors in the mature retina.

Human rod monochromacy: linkage analysis and mapping of a cone photoreceptor expressed candidate gene on chromosome 2q11.

We have performed linkage analysis in eight families with rod monochromacy, an autosomal recessively inherited condition with complete color blindness. Significant linkage was found with markers located at the pericentromeric region of chromosome 2. A maximum lod score of 5.36 was obtained for marker D2S2333 at theta = 0.00. Mapping of meiotic breakpoints localized the disease gene between markers D2S2187 and D2S2229. Homozygosity for a number of subsequent markers indicating identity by descent was found in two families and provides evidence for a further refinement of the locus proximal to D2S373. This defines an interval of approximately 3 cM covering the ACHM2 locus for rod monochromacy. Radiation hybrid mapping of the CNGA3 gene encoding the alpha-subunit of the cGMP gated cation channel in human cone photoreceptors resulted in a maximum lod score of 16.1 with marker D2S2311 combined with a calculated physical distance of 6.19cR10,000. Screening of the CEPH YAC library and subsequent STS mapping indicated the physical order cen-D2S2222-D2S2175-(D2S2187/D2S2311)-qtel ofmarkers on 2q11 and showed that the CNGA3 gene maps most closely to D2S2187 and D2S2311. These data indicate that the CNGA3 gene maps within the critical interval of the ACHM2 locus for rod monochromacy and thus is a candidate gene for this disease.

Naproxen in juvenile chronic polyarthritis.

Naproxen at 10 mg per kg body weight was compared with aspirin at 80 mg per kg body weight in children suffering from juvenile chronic polyarthritis. It was found to be as effective as aspirin, with certainly no more and possibly fewer gastrointestinal side effects. A long-term tolerance study up to 12 months confirmed that naproxed was a satisfactory nonsteroidal anti-inflammatory drug in the management of various types of juvenile chronic arthritis.

Naproxen absorption in children.

A study was carried out in 9 children (mean age 10.8 years) suffering from rheumatic disorders to determine peak plasma levels and plasma curve of naproxen following the administration of a single oral dose of a suspension formulation. The results suggest that there is no significant difference in naproxen peak blood levels and half-life between adults and children and a twice-daily dosage regime, as in adults, should be suitable, therefore, for therapeutic use in children. The formulation was well-tolerated and no untoward effects were noted.