Risk of chronic kidney disease in people living with HIV by tenofovir disoproxil fumarate (TDF) use and baseline D:A:D chronic kidney disease risk score.

OBJECTIVES: To assess the risk of chronic kidney disease (CKD) associated with tenofovir disoproxil fumarate (TDF) use by baseline D:A:D CKD risk score. METHODS: Adult antiretroviral therapy (ART)-naïve people living with HIV (PLWH) initiating treatment, with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 , were identified in the OPERA cohort. CKD was defined as two or more consecutive eGFR < 60 mL/min/1.73 m2 , > 90 days apart. Associations between TDF use, baseline D:A:D CKD risk and incident CKD were assessed with incidence rates (IRs; Poisson regression) and adjusted pooled logistic regression. The impact of pharmacoenhancers on the observed association between TDF and CKD was also evaluated. RESULTS: Of 9802 PLWH included, 6222 initiated TDF and 3580 did not (76% and 79% low D:A:D CKD risk, respectively). Overall, 125 CKD events occurred over 24 382 person-years of follow-up. Within strata of D:A:D CKD risk score, IRs were similar across TDF exposure, with high baseline CKD risk associated with highest incidence. Compared with the low-risk group without TDF, there was no statistical difference in odds of incident CKD in the low-risk group with TDF (adjusted odds ratio = 0.55, 95% confidence interval: 0.19-1.54). Odds of incident CKD did not differ statistically significantly by pharmacoenhancer exposure, with or without TDF. CONCLUSIONS: In this large cohort of ART-naïve PLWH, incident CKD following ART initiation was infrequent and strongly associated with baseline CKD risk. TDF-containing regimens did not increase the odds of CKD in those with a low baseline D:A:D CKD risk, the largest group of ART-naïve PLWH, and may remain a viable treatment option in appropriate settings.

Validation of the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) chronic kidney disease risk score in HIV-infected patients in the USA.

OBJECTIVES: The aim of the study was to assess the validity of an easy-to-calculate chronic kidney disease (CKD) risk score developed by the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) group in a longitudinal observational study of people living with HIV (PLWH) in the USA. METHODS: PLWH (2002-2016) without prior exposure to potentially nephrotoxic antiretroviral agents and with at least three estimated glomerular filtration rate (eGFR) test results were identified in the Observational Pharmaco-Epidemiology Research and Analysis (OPERA® ) cohort. Three samples were drawn independently using the same eligibility criteria but each using a different eGFR equation, specifically the Cockcroft-Gault (C-G), Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR estimation method. Full and short D:A:D risk scores were applied. CKD was defined as a confirmed decrease in eGFR to < 60 mL/min/1.73 m2 (stages 3-5). Poisson models estimated the association between CKD incidence and a one-point increase in the continuous risk score. The incidence rate ratio (IRR), adjusted IRR (aIRR), and Harrell's discrimination statistic were used to assess validity. RESULTS: There were 19 444, 22 727 and 22 748 PLWH in the OPERA C-G, CKD-EPI and MDRD samples, respectively. The median (minimum-maximum) follow-up duration was 6.1 (0.3-9.1) years in the D:A:D cohort and ranged from 3.2 to 3.5 (0.2-15.5) years in the OPERA validation samples. The observation time for the majority of PLWH in the D:A:D cohort began prior to 2006, in stark contrast to the OPERA validation samples, where the majority of PLWH were observed after 2011. The CKD incidence ranged from 7.3 per 1000 person-years [95% confidence interval (CI) 6.8, 7.9 per 1000 person-years] in OPERA C-G to 11.0 (95% CI 10.4, 11.6 per 1000 person-years) in OPERA MDRD. In OPERA samples, IRRs by risk group and adjusted IRRs (full risk score) were similar to those in the D:A:D derivation cohort (adjusted IRR 1.3; 95% CI 1.3, 1.3). Harrell's c-statistic ranged from 0.87 to 0.92 in the OPERA samples, comparable to that in the derivation cohort (0.92). Results for short scores were similar. CONCLUSIONS: The findings support the validity of the D:A:D risk scoring method for assessing CKD (stages 3-5) probability in an exclusively USA-based sample regardless of eGFR method.

Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients.

BACKGROUND: Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2-4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves. RESULTS: Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P =  0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P =  0.013). Early changes in serum IL-8 levels (2-4 weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P =  0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P =  0.001) and NSCLC (P =  0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression. CONCLUSIONS: Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.

Total and mutated EGFR quantification in cell-free DNA from non-small cell lung cancer patients detects tumor heterogeneity and presents prognostic value.

Mutation analysis of epidermal growth factor receptor (EGFR) gene is essential for treatment selection in non-small cell lung cancer (NSCLC). Analysis is usually performed in tumor samples. We evaluated the clinical utility of EGFR analysis in plasma cell-free DNA (cfDNA) from patients under treatment with EGFR inhibitors. We selected 36 patients with NSCLC and EGFR-activating mutations. Blood samples were collected at baseline and during treatment with EGFR inhibitors. Wild-type EGFR, L858R, delE746-A750, and T790M mutations were quantified in cfDNA by droplet digital PCR. Stage IV patients had higher total circulating EGFR copy levels than stage I (3523 vs. 1003 copies/mL; p < 0.01). There was high agreement for activating mutations between baseline cfDNA and tumor samples, especially for L858R mutation (kappa index = 0.679; p = 0.001). In 34 % of advanced NSCLC patients, we detected mutations in cfDNA not previously detected in tumor samples and double mutations in 17 %. Patients with baseline total EGFR copy levels above the median presented decreased overall survival (OS) (341 vs. 870 days, p < 0.05) and progression-free survival (PFS) (238 vs. 783 days; p < 0.05) compared with those with total EGFR copy levels below the median. Patients with baseline concentrations of activating mutations above the median (94 copies/mL) had lower OS (317 vs. 805 days; p < 0.05) and PFS (195 vs. 724 days; p < 0.05). During follow-up, T790M resistance mutation was detected in 53 % of patients. Total and mutated EGFR analysis in cfDNA seems a relevant tool to characterize the molecular profile and prognosis of NSCLC patients harboring EGFR mutations.

Antimicrobial susceptibility testing of clinical isolates of Bordetella pertussis from northern California: report from the SENTRY Antimicrobial Surveillance Program.

Reports of an increased clinical incidence of pertussis and the development of resistance by Bordetella pertussis to erythromycin prompted the collection and testing of recent clinical isolates from patients in northern California against a range of antimicrobial agents by the Etest (AB BIODISK, Solna, Sweden) method. All isolates were fully susceptible to all eight agents tested (MIC,

Mass vaccination of children with pertussis toxoid--decreased incidence in both vaccinated and nonvaccinated persons.

During 1979-1995, there was no vaccination against pertussis in Sweden. With the aim of studying the epidemiology and transmission of pertussis, mass vaccination with pertussis toxoid of children born during the 1990s was instituted in the Göteborg area (population, 778,597) in 1995. Infants were offered 3 doses of pertussis toxoid combined with diphtheria and tetanus toxoids. Children aged > or =1 year were offered 3 doses of pertussis toxoid alone. From June 1995 through February 1999, 167,810 doses of pertussis toxoid were given to 61,219 children born during the 1990s (56% received 3 doses). The number of Bordetella pertussis isolates per year declined from 1214 (1993-1995) to 64 (January 1997 through June 1999; P<.0001), and hospitalizations due to pertussis declined from 62 to 5 (P<.0001). Significant decreases in B. pertussis isolates and hospitalizations occurred in all age groups, including adults and nonvaccinated infants. Thus, mass vaccination of children with pertussis toxoid decreases spread of B. pertussis in the population.

Zidovudine and stavudine sequencing in HIV treatment planning: findings from the CHORUS HIV cohort.

BACKGROUND: Optimal sequencing of zidovudine and stavudine in antiretroviral therapy has not been elucidated. OBJECTIVE: To examine the impact of the sequence of therapeutic regimens containing zidovudine and stavudine on HIV-1 RNA and CD4 lymphocyte counts over 12 months. DESIGN: Observational, multicenter, longitudinal cohort study. SETTING: Four large outpatient, HIV practices participating in the community-based Collaborations in HIV Outcomes Research-U.S. (CHORUS) cohort study. PARTICIPANTS: 940 HIV-infected patients. METHODS: Comparison of HIV-1 RNA and CD4 lymphocyte responses in patients sequenced from zidovudine to stavudine or from stavudine to zidovudine using repeated measures regression models fit to outcomes by application of generalized estimating equation (GEE) methodology. RESULTS: Patients treated with zidovudine prior to stavudine (n = 834) achieved a greater mean drop from baseline HIV-1 RNA (p = .01) and higher proportion of undetectable HIV-1 RNA results (p = .05) over 12 months than those sequenced from stavudine to zidovudine (n = 106). CD4+ lymphocyte increases did not differ between the groups (p = .6). CONCLUSIONS: Prior zidovudine therapy was not associated with long-term attenuation of HIV-1 RNA or CD4 response to subsequent stavudine-containing regimens. Zidovudine before stavudine may have benefit in a strategic long-term therapeutic plan.

Autologous blood collection and transfusion in cats undergoing partial craniectomy.

OBJECTIVE: To describe the procedure for autologous blood donation and associated complications in cats undergoing partial craniectomy for mass removal. DESIGN: Prospective case series. ANIMALS: 15 cats with intracranial mass confirmed by computed tomographic scan, no evidence of renal failure, and PCV > or = 22%. PROCEDURE: One unit (60 ml) of blood was collected and stored 7 to 17 days before surgery and transfused during the perioperative period if needed. The PCV was measured before donation, before surgery, during surgery, and after surgery to assess effect of donation on PCV before surgery and effect of transfusion on PCV after surgery. Cats were evaluated for donation complications, iatrogenic anemia, and adverse reactions associated with administration of autologous blood. RESULTS: Complications associated with phlebotomy were not detected. Fifteen cats underwent partial craniectomy 7 to 17 days after blood donation; all had histologic confirmation of meningioma by examination of tissue obtained at surgery. Eleven cats received autologous blood transfusions. None of the cats received allogeneic blood transfusions. Transfusion reactions were not observed. Subclinical iatrogenic anemia was detected in 3 cats. Two cats were considered to have received excessive transfusion, and 3 cats received inadequate transfusion. All cats undergoing partial craniectomy were discharged from the hospital and were alive > 6 months after surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Autologous blood donation before surgery was considered safe for cats undergoing partial craniectomy for resection of meningioma. The only complication observed was iatrogenic anemia. The procedure contributed to blood conservation in our hospital.

DTaP vaccines from north american vaccine (NAVA): composition and critical parameters.

NAVA's acellular pertussis vaccine is based on highly purified pertussis toxin (PT) inactivated with H(2)O(2). PT was analysed using advanced biochemical methodology including mass spectroscopy (LC/MS), yielding mass and peptide mapping information on the subunits. Pertactin, adenylate cyclase, and Fim 1, 2 were below detection levels and only trace amounts of filamentous haemagglutinin (FHA) have been identified as a minor impurity. The vaccine does not induce anti-FHA antibodies during the course of a 3-dose primary immunization series in infants. B and T cell epitopes are preserved to a higher extent after H(2)O(2)detoxification when compared with chemical inactivation with formaldehyde, thus providing new information explaining why vaccines employing formaldehyde detoxified PT may need additional pertussis components added to induce high levels of protection. Anti-PT antibodies generated by NAVA diphtheria, tetanus, and acellular pertussis vaccine (DTaP) showed a positive correlation with protection against WHO-defined pertussis. The safety profiles for these vaccines showed low reactogenicity with no serious adverse events due to the vaccines.

Safety and immunogenicity of a new Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine in healthy adults.

UNLABELLED: We evaluated the safety and immunogenicity of a single dose of a new serogroup C O-deacetylated meningococcal polysaccharide-tetanus toxoid conjugate vaccine in 30 healthy adult volunteers. The vaccine was well tolerated with no serious adverse events and minimal local reactions and systemic symptoms. All subjects developed a fourfold or greater increase in serum bactericidal antibody (SBA) to serogroup C meningococcus. SBA geometric mean titre increased from 11 to 3649 (p<0.001). Serogroup C-specific IgG levels increased postvaccination from 0.65 to 17.02 microg/ml (p<0.001). Bactericidal titres pre- and postimmunisation showed significant correlation with serogroup C-specific IgG (r(2)=0.693). Antibody levels fell by 6 months postvaccination, however, meningococcal C IgG avidity increased indicating the successful induction of a T-cell-dependent antibody response. CONCLUSION: meningococcal C-tetanus toxoid conjugate vaccine is immunogenic and well tolerated in healthy adults.

Depression in Latina mothers of children with mental retardation: a neglected concern.

Depression among 148 Latina women who have children with mental retardation was examined. Results showed that their depressive symptomatology was elevated, with almost half reporting negative experiences in excess of a commonly used cut-off for the Center for Epidemiologic Studies Scale (CES-D). Depression scores related to variables pertaining to the child, mother's health and level of acculturation, and aspects of stress and coping. When mothers were categorized in three groups by CES-D scores, discriminant analysis correctly classified 84% of the low and high group mothers. High CES-D membership was predicted by mothers' reporting more family problems, worse health, fewer interactions with English-speaking persons in their daily lives, and more negative feelings about parenting their child with mental retardation.

Transpyloric spread of gastric tumors: comparison of adenocarcinoma and lymphoma.

OBJECTIVE: Our objective was to determine the relative frequency of transpyloric tumor spread in gastric antral carcinoma and lymphoma. MATERIALS AND METHODS: We reviewed the medical records of 127 cases of pathologically proven gastric malignant tumors, including 102 carcinomas and 25 lymphomas, over a 10-year period. The antrum had carcinoma in 64 cases and lymphoma in 15. We reviewed upper gastrointestinal barium studies and correlated the findings of transpyloric tumor extension with the results of surgery, pathology, and endoscopy. RESULTS: Tumor extension into the duodenal bulb occurred in 16 (25%) of 64 patients with carcinoma and in six (40%) of 15 patients with lymphoma of the gastric antrum. Transpyloric spread of antral carcinoma as revealed by barium study was much more common in our series than has been stated in the literature. CONCLUSION: Duodenal invasion of an antral carcinoma is not rare. Because of the higher incidence of carcinoma, transpyloric spread of gastric tumor as revealed by barium studied should not by itself suggest the diagnosis of lymphoma.

Osteopathic graduate medical education.

Osteopathic graduate medical education is still in transition. The AOA Department of Education will continue to monitor and report on the impact of these changes.